Chemoresistance

[Rich66]

(TK inhibs, Lapatanib, cox2 inhibs, prolactin/estrogen, retinoids, honokiol, nomegestrol, mTOR, chlororoquines, nitric oxide, Proton pump inhibitors, warburg/glycolysis, bitter melon, statins?. IGF, PI3k?, Bicyclol)


Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1529-42.
ABCG2: the key to chemoresistance in cancer stem cells?

An Y, Ongkeko WM.
Stanford University School of Medicine, Stanford, CA 94305, USA.


LINK

Abstract

Multi-drug chemoresistance remains one of the most common reasons for chemotherapy failure. The membrane transporter protein ABCG2/BCRP1 has been shown in vitro to effectively reduce the intracellular concentrations of several prominent anticancer chemotherapeutic agents such as mitoxantrone and doxorubicin. Intriguingly, cancer stem cells are known to be characterized by multi-drug chemoresistance. Taking into account that the ABCG2(+) subset of tumor cells are often enriched with cells with cancer stem-like phenotypes, it has been proposed that ABCG2 activity underlies the ability of cancer cells to regenerate post-chemotherapy. Furthermore, we also review evidence suggesting that tyrosine kinase inhibitors, including imatinib and gefitinib, are both direct and downstream inactivators of ABCG2 and, therefore, serve as candidates to reverse cancer stem cell chemoresistance and potentially target cancer stem cells.

PMID: 19708828 [PubMed - indexed for MEDLINE]



Cancer Res. 2008 Oct 1;68(19):7905-14.
Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.

Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW.
State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.


FREE TEXT


Erratum in:

• Cancer Res. 2008 Dec 15;68(24):10387.

Abstract

Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.

PMID: 18829547 [PubMed - indexed for MEDLINE]PMCID: PMC2652245Free PMC Article






Cell Oncol. 2009;31(6):457-65.
Cyclo-oxygenase 2 modulates chemoresistance in breast cancer cells involving NF-kappaB.

Zatelli MC, Molè D, Tagliati F, Minoia M, Ambrosio MR, degli Uberti E.
Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy.
BACKGROUND: Breast cancer cells can develop chemoresistance after prolonged exposure to cytotoxic drugs due to expression of the multi drug resistance (MDR) 1 gene. Type 2 cyclo-oxygenase (COX-2) inhibitors reverse the chemoresistance phenotype of a medullary thyroid carcinoma cell line, TT, and of a breast cancer cell line, MCF7, by inhibiting MDR1 expression and P-gp function. AIM: investigate the role of prostaglandin (PG) in modulating chemoresistance in MCF7 cells and to explore the involved intracellular mechanisms. METHODS: native and chemoresistant MCF7 cells were treated with PGH2 and resistance to Doxorubicin was tested in the presence or absence of COX-2 inhibitors. RESULTS: PGH2 restores resistance to the cytotoxic effects of Doxo, with concomitant nuclear translocation of the transcription factor NF-kappaB. CONCLUSIONS: COX-2 inhibitors prevent chemoresistance development in breast cancer cells by inhibiting P-gp expression and function by a mechanism that involves PGH2 generation and NF-kappaB activation.

PMID: 19940361 [PubMed - indexed for MEDLINE]




Endocr Relat Cancer. 2010 Jan 13. [Epub ahead of print]
Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy.

Lapensee E, Ben-Jonathan N.
E LaPensee, Cancer and Cell Biology, University of Cincinnati, Cincinnati, United States.
Resistance to chemotherapy is a major complication in the treatment of advanced breast cancer. Estrogens and prolactin (PRL) are implicated in the pathogenesis of breast cancer but their roles in chemoresistance have been overlooked. A common feature to the two hormones is activation of their receptors by diverse compounds which mimic or antagonize their actions. The PRL receptor (PRLR) is activated by lactogens (PRL, growth hormone or placental lactogen) originating from the pituitary, breast, adipose tissue or the placenta. Estrogen receptors (ERs) exist in multiple membrane-associated and cytoplasmic forms that can be activated by endogenous estrogens, man-made chemicals, and phytoestrogens. Here we review evidence that low doses of PRL, estradiol (E2), and bisphenol A (BPA) antagonize multiple anti-cancer drugs that induce cell death by different mechanisms. Focusing on cisplatin, a DNA-damaging drug which is effective in the treatment of many cancer types but not breast cancer, we compare the abilities of PRL, E2 and BPA to antagonize its cytotoxicity. Whereas PRL acts by activating the glutathione-S-transferase detoxification enzyme, E2 and BPA act by inducing the anti-apoptotic protein Bcl-2. The implications of these findings to patients undergoing chemotherapy are discussed.

PMID: 20071456 [PubMed - as supplied by publisher]



Canned Food May Expose People to BPA

http://www.medicinenet.com/script/ma...iclekey=116406

Quote:

A study conducted by a coalition of consumer and food safety groups found detectable levels of BPA in 46 of 50 grocery store cans tested. The results suggest BPA routinely leaches from can linings into food.
BPA has been associated with a variety of health problems in laboratory animals, including cancers, early puberty, and developmental problems.
The highest BPA level detected was 1,140 parts per billion, found in a can of Del Monte French Style Green Beans obtained from the pantry of a study participant in Wisconsin.

http://www.breastcancerfund.org/medi...-chemical.html


http://contaminatedwithoutconsent.or...lverlining.php





Breast Cancer Res. 2001;3(4):253-63. Epub 2001 Apr 2.
Reversal effects of nomegestrol acetate on multidrug resistance in adriamycin-resistant MCF7 breast cancer cell line.

Li J, Xu LZ, He KL, Guo WJ, Zheng YH, Xia P, Chen Y.
Xin Hua Hospital, Shanghai Second Medical University, Shanghai, China. ljee@citiz.net
BACKGROUND: Chemotherapy is important in the systematic treatment of breast cancer. To enhance the response of tumours to chemotherapy, attention has been focused on agents to reverse multidrug resistance (MDR) and on the sensitivity of tumour cells to chemical drugs. Hundreds of reversal drugs have been found in vitro, but their clinical application has been limited because of their toxicity. The reversal activity of progestogen compounds has been demonstrated. However, classical agents such as progesterone and megestrol (MG) also have high toxicity. Nomegestrol (NOM) belongs to a new derivation of progestogens and shows very low toxicity. We studied the reversal activity of NOM and compared it with that of verapamil (VRP), droloxifene (DRO), tamoxifen (TAM) and MG, and investigated the reversal mechanism, i.e. effects on the expression of the MDR1, glutathione S-transferase Pi (GSTpi), MDR-related protein (MRP) and topoisomerase IIalpha (TopoIIalpha) genes, as well as the intracellular drug concentration and the cell cycle. The aim of the study was to examine the reversal effects of NOM on MDR in MCF7/ADR, an MCF7 breast cancer cell line resistant to adriamycin (ADR), and its mechanism of action. METHODS: MCF7/ADR cells and MCF7/WT, an MCF7 breast cancer cell line sensitive to ADR, were treated with NOM as the acetate ester. With an assay based on a tetrazolium dye [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; MTT], the effects of various concentrations of NOM on MDR in MCF7/ADR cells were studied. Before and after the treatment with 5 microM NOM, the expression of the MDR-related genes MDR1, GSTpi, TopoIIalpha and MRP were assayed with a reverse transcriptase polymerase chain reaction (RT-PCR) immunocytochemistry assay. By using flow cytometry (FCM), we observed the intracellular ADR concentration and the effects of combined treatment with NOM and ADR on the cell cycle. Results collected were analysed with Student's t test. RESULTS: NOM significantly reversed MDR in MCF7/ADR cells. After treatment NOM at 20, 10 and 5 microM, chemosensitivity to ADR increased 21-fold, 12-fold and 8-fold, respectively. The reversal activity of NOM was stronger than that of the precursor compound MG, and comparable to that of VRP. After treatment with 5 microM NOM, the expression of both the MDR1 and the GSTpi mRNA genes began to decline on the second day (P <0.05 and P <0.01, respectively), and reached the lowest level on the third day (both P <0.01); however, on the fifth day the expression levels began to increase again (both P <0.05). The expression of MRP and TopoIIalpha had no significant changes. Changes in the expression of P-glycoprotein (P-gp) and GSTpi were similar to those of their mRNA expressions, showing early declines and late increases. Two hours after treatment with 20, 10 and 5 microM NOM, the intracellular ADR concentration increased 2.7-fold, 2.3-fold and 1.5-fold respectively. However, NOM did not increase ADR accumulation in MCF7/WT cells. FCM data showed that after 48 h of combined administration of NOM (20 microM) and ADR (from low to high concentration), MCF7/ADR cells showed a gradual arrest at the G2M phase with increasing ADR dose. The arrest effect with combined drug treatment was stronger than that with the single ADR treatment. CONCLUSION: MDR is the major mechanism of drug resistance in malignant tumour cells. To overcome MDR and to increase chemosensitivity, many reversal agents have been found. Most progestogen compounds have been demonstrated to have reversal effects, but we found no data on NOM, a new progestogen compound. Our results show that NOM has strong reversal activity. The reversal effects were stronger than those of the precursor compound, MG, and were comparable to that of VRP. Because NOM has low toxicity, it might have good prospects in clinical application. Using RT-PCR and immunocytochemistry assays, we studied the effects of NOM on MDR-related genes. The results were that NOM could markedly downregulate the mRNA and protein expression levels of MDR1 and GSTpi. TopoIIalpha and MRP gene expression showed no significant changes. It is known that P-gp induces MDR in tumour cells mainly by decreasing the intracellular drug concentration. After treatment with NOM, the intracellular drug concentration in MCF7/ADR cells increased significantly. Combined treatment with NOM and ADR induced arrest at the G2M phase. It is worth noting that NOM caused an early decrease and a late increase in the expression of some MDR-related genes in a time-dependent manner. The phenomena raise a question for the continued administration of reversal agents in clinics that merits further study. We demonstrate that NOM has strong reversal effects on MDR in MCF7/ADR cells. The reversal is via different routes, namely downregulating the mRNA and protein expression levels of MDR1 and GSTpi, increasing intracellular drug concentration and arresting cells at the G2M phase (NOM in combination with ADR). The reversal mechanism needs further study.

PMID: 11434876 [PubMed - indexed for MEDLINE]

1: Mol Cancer Ther. 2005 May;4(5):824-34. Links

The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma.

Yen WC, Lamph WW.
Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, CA 92121, USA.
Acquired drug resistance represents a major challenge in the therapeutic management of breast cancer patients. We reported previously that the retinoid X receptor-selective agonist bexarotene (LGD1069, Targretin) was efficacious in treating animal models of tamoxifen-resistant breast cancer. The goal of this study was to evaluate the effect of bexarotene on development of acquired drug resistance and its role in overcoming acquired drug resistance in advanced breast cancer. Paclitaxel, doxorubicin, and cisplatin were chosen as model compounds to determine the effect of bexarotene on the development of acquired drug resistance. Human breast cancer cells MDA-MB-231 were repeatedly treated in culture with a given therapeutic agent with or without bexarotene for 3 months. Thereafter, cells were isolated and characterized for their drug sensitivity. Compared with parental cells, cells treated with a single therapeutic agent became resistant to the therapeutic agent, whereas cells treated with the bexarotene combination remained chemosensitive. Cells with acquired drug resistance, when treated with the combination, showed increased sensitivity to the cytotoxic agent. Furthermore, cells treated with the combination regimen had reduced invasiveness and angiogenic potential than their resistant counterparts. These in vitro findings were further confirmed in an in vivo MDA-MB-231 xenograft model. Our results suggest a role for bexarotene in combination with chemotherapeutic agents in prevention and overcoming acquired drug resistance in advanced breast carcinoma.
PMID: 15897247 [PubMed - indexed for MEDLINE

J Cancer Res Clin Oncol. 2008 Sep;134(9):937-45. Epub 2008 Mar 19.
Liposomal honokiol, a promising agent for treatment of cisplatin-resistant human ovarian cancer.

Luo H, Zhong Q, Chen LJ, Qi XR, Fu AF, Yang HS, Yang F, Lin HG, Wei YQ, Zhao X.
Department of Gynecology and Obstetrics, West China Second Hospital and State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China. luohongcd1969@163.com
PURPOSE: Honokiol has been receiving attention as an anticancer agent because of its anti-tumor effect. In the current study, we encapsulated honokiol with liposome and tested it on cisplatin-sensitive (A2780s) and -resistant (A2780cp) human ovarian cancer models. METHODS: The anti-tumor activity of liposomal honokiol (Lipo-HNK) was evaluated in nude mice bearing A2780s and A2780cp s.c. tumors. Mice were treated twice weekly with i.v. administration of Lipo-HNK (10 mg/kg), control liposome (10 mg/kg), 0.9% NaCl solution or weekly with intraperitoneally administered cisplatin (5 mg/kg) for 3 weeks. Tumor volume and survival time were observed. Assessment of apoptotic cells by TUNEL assay was conducted in tumor tissue. Microvessel density within tumor tissue was determined by CD34 immunohistochemistry. For in vitro study, induction of apoptosis by Lipo-HNK was examined by PI staining fluorescence microscopy, DNA fragmentation assay and flow cytometric analysis. RESULTS: Administration of Lipo-HNK resulted in significant inhibition (84-88% maximum inhibition relative to controls) in the growth of A2780s and A2780cp tumor xenografts and prolonged the survival of the treated mice. These anti-tumor responses were associated with marked increases in tumor apoptosis, and reductions in intratumoral microvessel density. CONCLUSIONS: The present findings suggest that Lipo-HNK may provide an effective approach to inhibit tumor growth in both cisplatin sensitive and -resistant human ovarian cancer with minimal side effects.

PMID: 18350317 [PubMed - indexed for MEDLINE]






JOP. 2009 Jul 6;10(4):393-5.
Sirolimus can reverse resistance to gemcitabine, capecitabine and docetaxel combination therapy in pancreatic cancer.

Sherman WH.
Columbia University, College Physicians and Surgeons, New York, NY, USA. whs4@columbia.edu
CONTEXT: Treating patients with metastatic carcinoma of the pancreas can lead to regression of disease, but the tumor becomes resistant to therapy within a few months. If resistance can be reversed or prevented, the chemotherapeutic benefit may be prolonged. CASE REPORTS: Two patients with metastatic pancreatic cancer progressed on gemcitabine, capecitabine and docetaxel (GTX). When sirolimus was added to this regimen at a dosage to achieve a serum level of at least 10 ng/dL at the time of the gemcitabine and docetaxel infusion, their tumors regressed. CONCLUSION: This demonstrates that the addition of sirolimus to a gemcitabine/docetaxel containing regimen can reverse tumor resistance in the clinical setting.

PMID: 19581741 [PubMed - indexed for MEDLINE]

Distinguishing Friend from Foe in the Battle Against Cancer

http://www.physorg.com/news77201870.html

excerpt:

Rapamycin, an immunosuppressant used to block organ rejection after transplants, also inactivates proteins stimulating cell division and in clinical trials has been combined with other drugs to halt cancer cell growth.
But to cancer cells, rapamycin is both friend and foe. “Rapamycin is not as successful as initially expected in treating cancer,” explains Ghosh. “Instead of killing cells, you end up triggering a survival response in them.” This study, however, suggests that taking NF-kB out of the game would make rapamycin less “friendly.”
“A major problem of chemotherapy is that sooner or later cancer cells develop resistance, which requires higher and higher doses of chemotherapeutics,” observes Verma, who is also an American Cancer Society professor in Salk's Laboratory of Genetics. “Rapamycin-mediated killing of cancer cells could be increased by inhibiting the function of NF-kB proteins. Our studies provide the basis for arriving at this very important conclusion, which has enormous bearing on cancer treatment.”
Tergaonkar concurs. “Our studies suggest the potential use of NF-kB signaling inhibitors as adjuvants to maximize the effect of rapamycin-based therapeutics. These findings will have a significant impact on human health.”

See more on mTOR inhibitors and how Metformin may be better than Rapamycin.






Chloroquines (sensitizes to rads and chemo, HDAC inhib, blocks pumps)
http://her2support.org/vbulletin/showthread.php?t=42181






Cancer Chemother Pharmacol. 2004 Dec;54(6):525-30. Epub 2004 Jul 10.
Inhibition of P-glycoprotein activity and reversal of cancer multidrug resistance by Momordica charantia extract.

PURCHASE TEXT Bitter melon thread


Limtrakul P, Khantamat O, Pintha K.
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. plimtrak@mail.med.cmu.ac.th
PURPOSE: Multidrug resistance (MDR) is known as a problem limiting the success of therapy in patients treated long term with chemotherapeutic drugs. The drug resistance is mainly due to the overexpression of the 170 kDa P-glycoprotein (Pgp), which causes a reduction in drug accumulation in the cancer cells. In this study, novel chemical modulator(s) from bitter melon (Momordica charantia L.) extracts obtained from leaves, fruits and tendrils were tested for their abilities to modulate the function of Pgp and the MDR phenotype in the multidrug-resistant human cervical carcinoma KB-V1 cells (high Pgp expression) in comparison with wildtype drug-sensitive KB-3-1 cells (lacking Pgp). METHODS: The KB-V1 and KB-3-1 cells were exposed to bitter melon extracts in the presence of various concentrations of vinblastine, and cytotoxicity was assessed by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Relative resistance was calculated as the ratio of the IC50 value of the KB-V1 cells to the IC50 value of the KB-3-1 cells. Accumulation and efflux of vinblastine in KB-V1 and KB-3-1 cells were measured using a [3H]-vinblastine incorporation assay. RESULTS: The leaf extracts increased the intracellular accumulation of [3H]-vinblastine in KB-V1 cells in a dose-dependent manner, but extracts from the fruits and tendrils had no effect. By modulating Pgp-mediated vinblastine efflux, the leaf extracts decreased the [3H]-vinblastine efflux in KB-V1 cells in a dose-dependent manner, but not in KB-3-1 cells. Treatment of drug-resistant KB-V1 cells with bitter melon leaf extracts increased their sensitivity to vinblastine, but similar treatment of KB-3-1 cells showed no modulating effect. The fruit and tendril extracts did not affect the MDR phenotype in either cell line. CONCLUSION: The leaf extracts from bitter melon were able to reverse the MDR phenotype, which is consistent with an increase in intracellular accumulation of the drug. The exact nature of the active components of bitter melon leaf extracts remains to be identified.

PMID: 15248030 [PubMed - indexed for MEDLINE]





Clin Cancer Res. 2007 Apr 1;13(7):2199-206.
Chemosensitization of cancer in vitro and in vivo by nitric oxide signaling.

Frederiksen LJ, Sullivan R, Maxwell LR, Macdonald-Goodfellow SK, Adams MA, Bennett BM, Siemens DR, Graham CH.
Department of Anatomy, Queen's University, Kingston, Ontario, Canada.
PURPOSE: Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro. Classic NO signaling involves activation of soluble guanylyl cyclase, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinase. Here, we determined whether chemosensitization by NO mimetics requires cGMP-dependent signaling and whether low concentrations of NO mimetics can chemosensitize tumors in vivo. EXPERIMENTAL DESIGN: Survival of human prostate and breast cancer cells was assessed by clonogenic assays following exposure to chemotherapeutic agents. The effect of NO mimetics on tumor chemosensitivity in vivo was determined using a mouse xenograft model of human prostate cancer. Drug efflux in vitro was assessed by measuring intracellular doxorubicin-associated fluorescence. RESULTS: Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel. Similar to hypoxia-induced drug resistance, inhibition of various components of the NO signaling pathway increased resistance to doxorubicin, whereas activation of the pathway with 8-bromo-cGMP attenuated hypoxia-induced resistance. Drug efflux was unaffected by hypoxia and inhibitors of drug efflux did not significantly attenuate hypoxia-induced chemoresistance. Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch. The presence of GTN and GTN metabolites in plasma samples was confirmed by gas chromatography. CONCLUSION: Tumor hypoxia induces resistance to anticancer drugs by interfering with endogenous NO signaling and reactivation of NO signaling represents a novel approach to enhance chemotherapy.

PMID: 17404104 [PubMed - indexed for MEDLINE]


Article on human prostate cancer study with NO patch:
http://www.sciencedaily.com/releases...0209091844.htm

Of the 17 patients who completed the study, all but one showed a stabilization or decrease in the rate of cancer progression, as measured by their PSA Doubling Time.

Nitroglycerin has been used at significantly higher doses for more than a century to treat angina. This trial was based on a key finding from pre-clinical research carried out at Queen's, which showed that decreases in nitric oxide play an important role in tumor progression and that this progression can be stopped by low-dose nitroglycerin.

Breast Cancer Res Treat. 2006 Mar;96(2):169-76.
Nitric oxide attenuates resistance to doxorubicin in three-dimensional aggregates of human breast carcinoma cells.

Muir CP, Adams MA, Graham CH.
Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada.
Compared with monolayer culture, tumour cells cultured as multicellular aggregates (spheroids) exhibit much higher levels of resistance to chemotherapeutic agents, a phenomenon known as multicellular resistance (MCR). Associated with multicellular aggregates is a heterogeneous microenvironment characterised by gradients in oxygen, pH, and nutrients. We previously showed that nitric oxide (NO) signalling plays an important role in the regulation of chemosensitivity in cancer cells cultured as monolayer, and that hypoxia increases resistance to anti-cancer agents largely through a mechanism involving the inhibition of NO signalling. The goal of the present study was to determine whether NO mimetics chemosensitize breast cancer cells in spheroid cultures. Survival of MDA-MB-231 breast carcinoma cells was determined by clonogenic assay following spheroid culture, doxorubicin exposure, and NO mimetic administration. When spheroids were incubated for 24 h with the NO mimetics diethylenetriamine/nitric oxide adduct (DETA/NO) and glyceryl trinitrate (GTN), cell survival after doxorubicin (200 microM) exposure was decreased by 33% (p<0.006) and by up to 47% (p<0.02), respectively. Nitric oxide-mediated signalling involves the generation of the second messenger cyclic guanosine monophosphate (cGMP). Administration of a non-hydrolysable cGMP analogue, 8-Bromo-cGMP, significantly decreased MCR (p<0.04). The effect of NO mimetic exposure on tumour cell chemosensitivity was not due to increased penetration of doxorubicin into spheroids, nor was it associated with an increase in cell proliferation. These results suggest that NO mimetics attenuate MCR to doxorubicin through a mechanism involving cGMP-dependent signalling. Therefore, NO-mimetics may potentially be used as chemosensitizers in cancer therapy.

PMID: 16331349 [PubMed - indexed for MEDLINE]


Nitric Oxide. 2008 Sep;19(2):205-16. Epub 2008 May 6.
Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer.

Yasuda H.
Department of Translational Clinical Oncology, Kyoto University Graduate School of Medicine, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. yasuda@kuhp.kyoto-u.ac.jp
Hypoxia exists in solid tumor tissues due to abnormal vasculature, vascular insufficiency, treatment or malignancy related anemia, and low intratumor blood flow. Hypoxic status in solid tumor promotes accumulation of hypoxia-inducible factor-1 alpha which is promptly degraded by proteasomal ubiquitination under normoxic conditions. However, under hypoxic conditions, the ubiquitination system for HIF-1 alpha is inhibited by inactivation of prolyl hydroxylase which is responsible for hydroxylation of proline in the oxygen-dependent degradation domain of HIF-1 alpha. HIF-1 alpha is an important transcriptional factor that codes for hundreds of genes involved in erythropoiesis, angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis. Hypoxia and accumulation of HIF-1 alpha in solid tumor tissues have been reported to associate with resistance to chemotherapy, radiotherapy, and immunotherapy and poor prognosis. Production of vascular endothelial growth factor (VEGF) in cancer cells is regulated by the activated HIF-1 mediated system. An increase in VEGF levels subsequently induces HIF-1 alpha accumulation and promotes tumor metastasis by angiogenesis. Recently, angiogenesis targeting therapy using humanized VEGF antibody and VEGF receptor tyrosine kinase inhibitors have been used in solid cancer therapy. Nitric oxide (NO) is a unique chemical gaseous molecule that plays a role as a chemical messenger involved in vasodilator, neurotransmitter, and anti-platelet aggregation. In vivo, NO is produced and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors. In cancer science, NO has been mainly discussed as an oncogenic molecule over the past decades. However, NO has recently been noted in cancer biology associated with cancer cell apoptosis, cancer cell cycle, cancer progression and metastasis, cancer angiogenesis, cancer chemoprevention, and modulator for chemo/radio/immuno-therapy. The presence and activities of all the three isoforms of NOS and were detected in cancer tissue components such as cancer cells, tumor-associated macrophages, and vascular endothelium. Overexpression of iNOS in cancer tissues has been reported to associate with poor prognosis in patients with cancers. On the other hand, NO donors such as nitroglycerin have been demonstrated to improve the effects of cancer therapy in solid cancers. Nitroglycerin has been used safely for a long time as a potent vasodilator for the treatment of ischemic heart diseases or heart failure. Therefore, we think highly of clinical use of nitroglycerin as a novel cancer therapy in combination with anticancer drugs for improvement of cancer therapeutic levels. In this review article, we demonstrate the unique physiological characteristics of malignant solid tumors, several factors in solid tumors resulting in resistance for cancer therapies, and the effects of NO from NOS or exogenous NO-donating drugs on malignant cells. Furthermore, we refer to promising therapeutic roles of NO and NO-donating drugs for novel treatments in solid tumors.

PMID: 18503779 [PubMed - indexed for MEDLINE]

More on above HERE







Expert Opin Pharmacother. 2005 Jun;6(7):1049-54.
Proton pump inhibitors may reduce tumour resistance.

De Milito A, Fais S.
Resistance to cytotoxic agents is a major problem in treating cancer. The mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis. A mechanism of resistance may be alteration of the tumour microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm. The extracellular pH of solid tumours is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumours. An option to revert multi-drug resistance is the use of agents that disrupt the pH gradient in tumours by inhibiting the function of pumps generating the pH gradient, such as vacuolar H(+)-ATPases (V-H(+)-ATPases). PPIs (including omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) are protonable weak bases which selectively accumulate in acidic spaces. Recent findings from our group have shown that PPI pretreatment sensitised tumour cell lines to the effect of cisplatin, 5-fluoro-uracil and vinblastine V-H(+)-ATPases pump protons across the plasma membrane and across the membranes of various intracellular compartments. Some human tumour cells, particularly those selected for multi-drug resistance, exhibit enhanced V-H(+)-ATPase activity. A class of V-H(+)-ATPase inhibitors, called proton pump inhibitors (PPIs), have emerged as the drug class of choice for treating patients with peptic diseases. These drugs inhibit gastric acid secretion by targeting the gastric acid pump, but they also directly inhibit V-H(+)-ATPases.. PPI pretreatment was associated with the inhibition of V-H(+)-ATPase activity and an increase of both extracellular pH and the pH of lysosomal organelles, consistent with a cytoplasmic retention of the cytotoxic drugs and targeting to the nucleus in the case of doxorubicin. In vivo experiments showed that oral pretreatment with omeprazole induced a sensitivity of the human solid tumours to anticancer drugs.

PMID: 15957961 [PubMed - indexed for MEDLINE]


More on proton pump inhibitors HERE






Mol Cancer Ther. 2010 Jan 26. [Epub ahead of print]
Human Mutations That Confer Paclitaxel Resistance.

Yin S, Bhattacharya R, Cabral F.
Authors' Affiliation: Department of Integrative Biology and Pharmacology, and Graduate School of Biomedical Sciences, University of Texas Medical School, Houston, Texas.
The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether beta1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in beta1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in beta1-tubulin may require higher drug concentrations for effective therapy. Mol Cancer Ther; 9(2); OF1-9.

PMID: 20103599 [PubMed - as supplied by publisher]








Not sure how this can be accomplished but....

Published online before print January 25, 2010, doi: 10.1073/pnas.0910649107
Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

http://www.pnas.org/content/107/6/2503.short?rss=1

1. Nish Patel,Sabarni K. Chatterjee¹,Vladimir Vrbanac,Ivy Chung,Chunyao Jenny Mu,
2. Rachelle R. Olsen,Carol Waghorne², and Bruce R. Zetter³

+ Author Affiliations

1. Vascular Biology Program, Children’s Hospital Boston, Boston, MA 02115

• ↵ ¹Present address: National Institutes of Health, Rockville, MD 20852.
• ↵ ²Present address: ArQule, Woburn, MA 01801.

1. Edited by Rakesh K. Jain, Harvard Medical School, Boston, MA, and approved December 30, 2009 (received for review September 17, 2009)

Abstract

Paclitaxel has emerged as a front line treatment for aggressive malignancies of the breast, lung, and ovary. Successful therapy of cancer is frequently undermined by the development of paclitaxel resistance. There is a growing need to find other therapeutic targets to facilitate treatment of drug-resistant cancers. Using a proteomics approach, elevated levels of Prohibitin1 (PHB1) and GSTπ were found associated with paclitaxel resistance in discrete subcellular fractions of two drug-resistant sublines relative to their sensitive sublines. Immunofluorescence staining and fractionation studies revealed increased levels of PHB1 on the surface of resistant cell lines. Transiently silencing either PHB1 or GSTπ gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTπ resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTπ significantly improved paclitaxel sensitivity in A549TR cells both in vitro and in vivo. Our results indicate that PHB1 is a mediator of paclitaxel resistance and that this resistance may depend on the cellular localization of the protein. We suggest PHB1 as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.

To whom correspondence should be addressed. E-mail: bruce.zetter@childrens.harvard.edu.



Int J Cancer. 2008 May 1;122(9):1923-30.
Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis.

Gregory-Bass RC, Olatinwo M, Xu W, Matthews R, Stiles JK, Thomas K, Liu D, Tsang B, Thompson WE.
Department of Obstetrics and Gynecology, Cooperative Reproductive Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Current approaches to the treatment of ovarian cancer are limited because of the development of resistance to chemotherapy. Prohibitin (Phb1) is a possible candidate protein that contributes to development of drug resistance, which could be targeted in neoplastic cells. Phb1 is a highly conserved protein that is associated with a block in the G0/G1 phase of the cell cycle and also with cell survival. Our study was designed to determine the role of Phb1 in regulating cellular growth and apoptosis in ovarian cancer cells. Our results showed that Phb1 content is differentially overexpressed in papillary serous ovarian carcinoma and endometrioid ovarian adenocarcinoma when compared to normal ovarian epithelium and was inversely related to Ki67 expression. Immunofluorescence microscopy and Western analyses revealed that Phb1 is primarily associated with the mitochondria in ovarian cancer cells. Over-expression of Phb1 by adenoviral Phb1 infection resulted in an increase in the percentage of ovarian cancer cells accumulating at G0/G1 phase of the cell cycle. Treatment of ovarian cancer cells with staurosporine (STS) induced apoptosis in a time-dependent manner. Phb1 over-expression induced cellular resistance to STS via the intrinsic apoptotic pathway. In contrast, silencing of Phb1 expression by adenoviral small interfering RNA (siRNA) sensitized ovarian cancer cells to STS-induce apoptosis. Taken together, these results suggest that Phb1 induces block at G0/G1 phase of the cell cycle and promotes survival of cancer cells. Furthermore, silencing of the Phb1 gene expression may prove to be a valuable therapeutic approach for chemoresistant ovarian cancer by increasing sensitivity of cancer cells to apoptosis. (c) 2008 Wiley-Liss, Inc.

PMID: 18183577 [PubMed - indexed for MEDLINE]



Mol Cancer. 2010 Feb 9;9(1):33. [Epub ahead of print]
Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol.

Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, Riker AI, Kamarajugadda S, Lu J, Owen LB, Ledoux SP, Tan M.
ABSTRACT: BACKGROUND: Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells. RESULTS: Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells. CONCLUSION: LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.

PMID: 20144215 [PubMed - as supplied by publisher]


Related?:

Oncogene. 2009 Oct 22;28(42):3689-701. Epub 2009 Aug 10.
Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth.

Zhao YH, Zhou M, Liu H, Ding Y, Khong HT, Yu D, Fodstad O, Tan M.
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

PMID: 19668225 [PubMed - indexed for MEDLINE]






Antibiotic resistance reversal agents, chemotherapy resistance
reversal agents
A. Multidrug resistance protein-1 (MRP-1) inhibitors
1. genistein, other isoflavones (Glycine max)
B. P-glycoprotein inhibitors
1. Feijoa sellowiana pericarpium (Motohashi, et al. 2000)
2. Ficus citrifolia
3. indole-3-carbinol
4. quercetin
5. reserpine (Rauvolfia serpentina)
6. Rosmarinus officinalis
7. theanine (Camellia sinensis)
C. Miscellaneous
1. apigenin
2. berberine and flavonoids (Berberis spp)
3. curcumin
4. 3,7-dihydroxyflavone (Liu, et al. 2001)
5. flavone
6. galangin (Liu, et al. 2001)
7. genistein
8. kaempferol
9. verapamil



Med Hypotheses. 2010 Feb;74(2):237-9. Epub 2009 Oct 30.
Overcoming multidrug-resistance in cancer: statins offer a logical candidate.

Mehta NG, Mehta M.
3B/33 Takshila, Off, Mahakali Caves Road, Andheri (East), Maharashtra, India. ngmehta@rediffmail.com
About seven million people die of cancer every year. This is largely due to development of drug resistance, particularly multidrug resistance, in the tumor cells. Multidrug resistance (MDR) arises due to over-expression of MDR proteins in the cancer cells, which cause efflux of anticancer drugs from the cells using ATP. MDR proteins are members of the family of ABC transporters that occur universally, and are structurally and functionally conserved during evolution. In Drosophila, the germ cell attractant peptide is secreted by an ABC transport protein, mdr49. Recently, the peptide has been shown to undergo conjugation with the lipid geranylgeranyl before secretion. If conjugation with the lipid is inhibited, mdr49 protein is unable to transport the peptide. Similarly, in the case of yeast mating factor pheromone, farnesylation is required to occur before the export of the pheromone by ste6 protein, an ABC transporter. In view of the homology of mdr49 and ste6 proteins with mammalian MDR proteins, we postulate that the drug transporters also require their ligands to be conjugated to a lipid. This view finds support from the studies with synthetic inhibitors of geranylgeranyl-/farnesyl-diphosphate synthetase or transferase: The inhibitors are reported to overcome multidrug resistance in cancer cell lines or xenografts in animals. Thus, the MDR transporters also appear to require their substrates to be conjugated with a lipid. Statins are the widely used inhibitors of HMG-CoA reductase. By depleting precursors of the mevalonate pathway, statins can prevent the formation of lipids like geranylgeranyl and farnesyl. Accordingly, they should also be able to overcome multidrug resistance in cancer. A few reports in the literature indicate that they appear to do so. Statins are in wide clinical use, and their pharmacology is well known. Besides, statins per se have mild beneficial effect on the outcome of the disease. We propose that statins should be seriously investigated for their ability to overcome multidrug resistance in cancer. This should be done after careful standardization of the protocol of simultaneous treatment with anticancer drugs and a statin.

PMID: 19879695 [PubMed - in process]

1: Eur J Gynaecol Oncol. 2001;22(5):347-9.Links

Herbal complex suppresses telomerase activity in chemo-endocrine resistant cancer cell lines.

Lian Z, Fujimoto J, Yokoyama Y, Niwa K, Tamaya T.
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu City, Japan.
A herbal complex consisting of Hoelen, Angelicae radix, Scutellariae radix and Glycyrrhizae radix suppressed cell viability and telomerase activity in hormone-refractory and chemo-resistant cancer cell lines, namely poorly differentiated uterine endometrial cancer cell line AN3 CA, adriamycin-resistant breast cancer cell line MCF7/ADR and cisplatin-resistant ovarian cancer cell line A2780. Furthermore, the herbal complex suppressed the expression of the full length of human telomerase reverse transcriptase (hTERT), which is related to telomerase activity. This indicates that the herbal complex can suppress the tumor growth of chemoendocrine resistant cancers, at least in part via suppression of telomerase activity associated with down-regulated hTERT.
PMID: 11766737

Surprise!

Herbal mix has patent: http://www.freepatentsonline.com/7527812.html

[Rich66]

Front Biosci. 2008 May 1;13:3273-87.
The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance.

Casa AJ, Dearth RK, Litzenburger BC, Lee AV, Cui X.
Breast Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract

The insulin-like growth factor (IGF) ligands stimulate cellular proliferation and survival by activating the type I insulin-like growth factor receptor (IGF-IR). As a result, the IGF signaling system is implicated in a number of cancers, including those of the breast, prostate, and lung. In addition to mitogenic and anti-apoptotic roles that may directly influence tumor development, IGF-IR also appears to be a critical determinant of response to numerous cancer therapies. This review describes the role of the IGF-IR pathway in mediating resistance to both general cytotoxic therapies, such as radiation and chemotherapy, and targeted therapies, such as tamoxifen and trastuzumab. It concludes with a description of approaches to target IGF-IR and argues that inhibition of IGF signaling, in conjunction with standard therapies, may enhance the response of cancer cells to multiple modalities.

PMID: 18508432 [PubMed - indexed for MEDLINE]


Clin Pharmacol Ther. 2008 May;83(5):673-91. Epub 2007 Sep 5.
Recent advances on the molecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies.

Mimeault M, Hauke R, Batra SK.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA. mmimeault@unmc.edu


FREE TEXT

Abstract

This review summarizes the recent knowledge obtained on the molecular mechanisms involved in the intrinsic and acquired resistance of cancer cells to current cancer therapies. We describe the cascades that are often altered in cancer cells during cancer progression that may contribute in a crucial manner to drug resistance and disease relapse. The emphasis is on the implication of ATP-binding cassette (ABC) multidrug efflux transporters in drug disposition and antiapoptotic factors, including epidermal growth factor receptor cascades and deregulated enzymes in ceramide metabolic pathways. The altered expression and activity of these signaling elements may have a critical role in the resistance of cancer cells to cytotoxic effects induced by diverse chemotherapeutic drugs and cancer recurrence. Of therapeutic interest, new strategies for reversing the multidrug resistance and developing more effective clinical treatments against the highly aggressive, metastatic, and recurrent cancers, based on the molecular targeting of the cancer progenitor cells and their further differentiated progeny, are also described.

PMID: 17786164 [PubMed - indexed for MEDLINE]PMCID: PMC2839198Free PMC Article



Exp Cell Res. 2010 Aug 22. [Epub ahead of print]
Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression.
McDonald GT, Sullivan R, Paré GC, Graham CH.





Abstract
Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells following exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G(1) phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27(Kip1), and knockdown of p27(kip1) with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) is a critical determinant of chemosensitivity.

PMID: 20736003 [PubMed - as supplied by publisher]



Cancer Biol Ther. 2006 May;5(5):536-43. Epub 2006 May 5.
Chemosensitizing multiple drug resistance of human carcinoma by Bicyclol (schizandrin C) involves attenuated p-glycoprotein, GST-P and Bcl-2.

Zhu B, Liu GT, Zhao YM, Wu RS, Strada SJ.
University of South Alabama College of Medicine, Department of Pharmacology, Mobile, Alabama 36688, USA. zbing@jaguar1.usoutha1.edu


FREE TEXT

Abstract

Bicyclol, a second generation of synthetic hepatoprotectant being used in China for anti-hepatitis therapy, shows chemosensitizing effect on reverting multiple drug resistance (MDR) of cytostatic agents in two established MDR carcinoma cell lines, vincristine resistant human stomatic epidermoid carcinoma VinRKB and adriamycin resistant human breast carcinoma AdrRMCF-7. The reversal rate of drug resistance was calculated from the changes of the IC50 of cell growth inhibition. Bicyclol at the concentration of 25, 50, 100 microM induced 2.8 7.3 and 20.7 fold, respectively, reversal of vincristine resistance in VinRKB cell. Bicyclol also reversed the cross-resistance of VinRKB cell to taxol and AdrRMCF-7 cell resistance to adriamycin at the similar range of potency. Further, Bicyclol recovered the reduced accumulation of adriamycin in AdrRMCF-7 cell partially to the level in drug-sensitive MCF-7 cell, indicate the inhibition of MDR related membrane efflux pump system. Overexpression of membrane p-glycoprotein coded by Mdr-1 genes, the most common efflux pump correlated to MDR, was found in both VinRKB and AdrRMCF-7 cells by Western blot and immunocytochemistry as compared with drug-sensitive cells. The p-glycoprotein was decreased to the levels in drug-sensitive cells when VinRKB and AdrRMCF-7 cells were treated with Bicyclol for 12-72 hours. Both VinRKB and AdrRMCF-7 cells showed increased GSH contents, and AdrRMCF-7 cell showed increased GST activity and the overexpression of Bcl-2 protein, by which molecules are tightly related to the MDR formation besides Mdr-1 p-glycoprotein. Bicyclol reduced the GSH contents, GST activities and Bcl-2 expression. All these data demonstrate that, by modifying the expressions of Mdr-1, GSH/GST and Bcl-2, Bicyclol increases the intracellular drug concentration and sensitizes the resistant cells to the anti-carcinoma agents.

PMID: 16627975 [PubMed - indexed for MEDLINE]


Schisandra Fruit (bai wu wei zi)
http://www.tcmtreatment.com/herbs/0-wuweizi.htm




Carbohydr Res. 2009 Sep 28;344(14):1788-91. Epub 2008 Sep 26.
Modified citrus pectin anti-metastatic properties: one bullet, multiple targets.

Glinsky VV, Raz A.
Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.


LINK

Abstract

In this minireview, we examine the ability of modified citrus pectin (MCP), a complex water soluble indigestible polysaccharide obtained from the peel and pulp of citrus fruits and modified by means of high pH and temperature treatment, to affect numerous rate-limiting steps in cancer metastasis. The anti-adhesive properties of MCP as well as its potential for increasing apoptotic responses of tumor cells to chemotherapy by inhibiting galectin-3 anti-apoptotic function are discussed in the light of a potential use of this carbohydrate-based substance in the treatment of multiple human malignancies.


Swiss Med Wkly. 2011 May 31;141:w13208. doi: 10.4414/smw.2011.13208.
Cyclopamine reverts acquired chemoresistance and down-regulates cancer stem cell markers in pancreatic cancer cell lines.

Yao J, An Y, Wie JS, Ji ZL, Lu ZP, Wu JL, Jiang KR, Chen P, Xu ZK, Miao Y.

FREE TEXT

Source

Center for Pancreatic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, CN. docyao@126.com.

Abstract

BACKGROUND:

The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that Hh plays an important role in maintaining the cancer stem cell (CSCs) pool. Gemcitabine-resistant pancreatic cancer cells highly express some of the CSCs markers. However, the expression level of Hh members in gemcitabine-resistant pancreatic cancer cells remains unknown. The aim of this study was to verify the expression of HH members, such as Shh, Ptc, SMO and Gli-1 in gemcitabine-resistant PDAC cell lines, and to explore a new strategy to overcome chemoresistance in PDAC.
MATERIAL AND METHODS:

Quantitative real-time RT-PCR (Q-PCR) and western blot were used to evaluate the relative expression level of HH members in SW1990, CFPAC-1 cells and gemcitabine-resistant SW1990, CFPAC-1 cells. The change of cancer stem cell markers and the expression level of HH members before and after cyclopamine treatment was evaluated using flow cytometry and Q-PCR, western blot, respectively. Cell apoptosis after cyclopamine treatment was measured by flow cytometry.
RESULTS:

CD44, CD133 and the expression level of HH members, including Shh, SMO, Gli-1, were found to be highly expressed in gemcitabine-resistant cells, which were significantly down-regulated by cyclopamine treatment. Flow cytometry analysis showed increased cell apoptosis after cyclopamine treatment.
CONCLUSION:

Gemcitabine-resistant pancreatic cancer cells highly express CSCs markers and some of the HH members, and inhibition of HH by cyclopamine is an effective method of reversing gemcitabine resistance in pancreatic cancer.

PMID:21630164

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.Int J Med Sci. 2011 Mar 23;8(3):245-53.
Current status of methods to assess cancer drug resistance.

Lippert TH, Ruoff HJ, Volm M.

FREE TEXT

Source

Medical Faculty, University of Tübingen, Tübingen, Germany. Theodor-Lippert@web.de

Abstract

Drug resistance is the main cause of the failure of chemotherapy of malignant tumors, resistance being either preexisting (intrinsic resistance) or induced by the drugs (acquired resistance). At present, resistance is usually diagnosed during treatment after a long period of drug administration. In the present paper, methods for a rapid assessment of drug resistance are described. Three main classes of test procedures can be found in the literature, i.e. fresh tumor cell culture tests, cancer biomarker tests and positron emission tomography (PET) tests. The methods are based on the evaluation of molecular processes, i.e. metabolic activities of cancer cells. Drug resistance can be diagnosed before treatment in-vitro with fresh tumor cell culture tests, and after a short time of treatment in-vivo with PET tests. Cancer biomarker tests, for which great potential has been predicted, are largely still in the development stage. Individual resistance surveillance with tests delivering rapid results signifies progress in cancer therapy management, by providing the possibility to avoid drug therapies that are ineffective and only harmful.

PMID:

21487568

[PubMed - in process]

PMCID: PMC3074090

J Med Chem. 2012 Apr 12;55(7):3113-21. Epub 2012 Mar 22.
Synthesis and Evaluation of (2-(4-Methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (NSC23925) Isomers To Reverse Multidrug Resistance in Cancer.

Duan Z, Li X, Huang H, Yuan W, Zheng SL, Liu X, Zhang Z, Choy E, Harmon D, Mankin H, Hornicek F.

LINK

Source

Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.

Abstract

Development of multidrug resistance (MDR) during chemotherapy is a fundamental obstacle associated with cancer care. Prior studies have identified (2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (5) (NSC23925) to be a small molecule agent that reverses MDR in cancer cells. We synthesized all four isomers of 5 and analyzed them by liquid chromatography-mass spectrometry (LCMS). Structure-activity relationships for reversing MDR were evaluated. Isomer 11 demonstrated the most potent activity. 11 reversed MDR in several drug-resistant cell lines expressing Pgp, including ovarian, breast, colon, uterine, and sarcoma cancer. 11 resensitized these cell lines to paclitaxel, doxorubicin, mitoxantrone, vincristine, and trabectedin with no effect on cell sensitivity to cisplatin, topotecan, and methotrexate. 11 significantly enhanced in vivo antitumor activity of paclitaxel in MDR xenograft models, without increasing the level of paclitaxel toxicity. In conclusion, 11 and derivatives of this compound may hold therapeutic value in the treatment of MDR-dependent cancers.

PMID:

22400811

[PubMed - in process]

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