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Rich66 · 05-19-2010, 11:45 PM

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

05-19-2010, 11:45 PM	#2
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Chemoresistance 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 __________________ Mom's treatment history (link)