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Old 12-01-2009, 10:01 PM   #1
Rich66
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Chloroquine (s)

(sensitizes to rads and chemo, HDAC inhib, blocks pumps, Combats chemo probms via TLR9 inhibitor, w/5FU, w/AKt inhibs, requires specific dosing and monitoring)


Eur J Pharmacol. 2009 Dec 25;625(1-3):220-33. Epub 2009 Oct 15.
Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies.

Solomon VR, Lee H.
Tumor Biology Group, Northeastern Ontario Regional Cancer Program at the Sudbury Regional Hospital, 41 Ramsey Lake Road, Sudbury, Ontario, Canada P3E 5J1.
Chloroquine (CQ), N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely used as an effective and safe anti-malarial and anti-rheumatoid agent. CQ was discovered 1934 as "Resochin" by Andersag and co-workers at the Bayer laboratories. Ironically, CQ was initially ignored for a decade because it was considered too toxic to use in humans. CQ was "re-discovered" during World War II in the United States in the course of anti-malarial drug development. The US government-sponsored clinical trials during this period showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. Consequently, CQ was introduced into clinical practice in 1947 for the prophylaxis treatment of malaria (Plasmodium vivax, ovale and malariae). CQ still remains the drug of choice for malaria chemotherapy because it is highly effective and well tolerated by humans. In addition, CQ is widely used as an anti-inflammatory agent for the treatment of rheumatoid arthritis, lupus erythematosus and amoebic hepatitis. More recently, CQ has been studied for its potential as an enhancing agent in cancer therapies. Accumulating lines of evidence now suggest that CQ can effectively sensitize cell-killing effects by ionizing radiation and chemotherapeutic agents in a cancer-specific manner. The lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity. Although more studies are needed, CQ may be one of the most effective and safe sensitizers for cancer therapies. Taken together, it appears that the efficacy of conventional cancer therapies can be dramatically enhanced if used in combination with CQ and its analogs.

PMID: 19836374 [PubMed - in process]




BMC Cancer. 2010 Jul 15;10:370.
Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells.

Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai K, Okaji Y, Nishikawa T, Shuno Y, Hongo K, Hiyoshi M, Kaneko M, Kitayama J, Takahashi K, Nagawa H.
Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, Tokyo 113-8655, Japan. sasakik-sur@h.u-tokyo.ac.jp


FREE TEXT

Abstract

BACKGROUND: Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells.
METHODS: HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed.
RESULTS: 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21Cip1 and p27Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU.
CONCLUSION: Our findings suggest that the combination therapy with CQ should be a novel therapeutic modality to improve efficacy of 5-FU-based chemotherapy, possibly by inhibiting autophagy-dependent resistance to chemotherapy.

PMID: 20630104 [PubMed - in process]PMCID: PMC2914703Free PMC Article




Future Oncol. 2009 Dec;5(10):1685-704.
New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents.

Gurova K.
Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. katerina.gurova@roswellpark.org


Abstract

Most of the anticancer chemotherapeutic drugs that are broadly and successfully used today are DNA-damaging agents. Targeting of DNA has been proven to cause relatively potent and selective destruction of tumor cells. However, the clinical potential of DNA-damaging agents is limited by the adverse side effects and increased risk of secondary cancers that are consequences of the agents' genotoxicity. In this review, we present evidence that those agents capable of targeting DNA without inducing DNA damage would not be limited in these ways, and may be as potent as DNA-damaging agents in the killing of tumor cells. We use as an example literature data and our own research of the well-known antimalarial drug quinacrine, which binds to DNA without inducing DNA damage, yet modulates a number of cellular pathways that impact tumor cell survival.

PMID: 20001804 [PubMed - indexed for MEDLINE]PMCID: PMC2821823 [Available on 2010/10/1]






Curr Opin Investig Drugs. 2009 Dec;10(12):1269-79.
Autophagy inhibition in combination cancer treatment.

Livesey KM, Tang D, Zeh HJ, Lotze MT.
University of Pittsburgh, G.27A Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. LotzeMT@upmc.edu.
The effective elimination of cancer cells is compromised by mechanisms of resistance. Such mechanisms have been variably ascribed to drug export transporters, more effective DNA repair mechanisms compared with healthy cells, singularly resistant stem cells, resistance to apoptosis, self-sufficiency for growth factor signaling and an angiogenic switch, as well as immunological pathways associated with T-regulatory cells, myeloid-derived suppressor cells or plasmacytoid dendritic cells. In this review, the critically important process of autophagy, which is a mechanism of cell survival in the presence of genomic injury, endoplasmic reticulum stress, oxidant stress, nutrient insufficiency and viral/bacterial infection, is explored in the setting of cancer treatment. Autophagy has recently been demonstrated as important for conferring resistance to chemotherapy, radiation therapy and immunotherapy. Compounds are now available that can reverse autophagy, including the antimalarial compounds chloroquine and hydroxychloroquine, as well as the antidepressant agent clomipramine. Other strategies for the reversal of autophagy are based on the recent observation that the cytosolic location of the chromatin-binding protein HMGB1 (high-mobility group box-1) is associated with sustained autophagy. Targeting HMGB1 using platinum-containing compounds, ethyl pyruvate or glycyrrhizin has also been used to limit autophagy. Screening for new agents is ongoing, which, coupled with conventional chemotherapeutic compounds, may usher in a new generation of autophagy-inhibiting agents.

PMID: 19943199 [PubMed - in process]





Eur J Med Chem. 2009 Nov 11. [Epub ahead of print]
A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells.

Hu C, Raja Solomon V, Cano P, Lee H.
Tumour Biology, Northeastern Ontario Regional Cancer Program at the Sudbury Regional Hospital, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada.
The purpose of this study was to evaluate the enhancement value of chloroquine analogs when used in combination with Akt inhibitors on the MDA-MB468, MDA-MB231 and MCF7 human breast cancer cell lines. The result showed that the combination of certain chloroquine analogs and Akt inhibitors are highly effective. In particular, the chloroquine analog N'-(7-fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine (compound 5) was highly effective in sensitizing cancer cell killing when combined with either Akt inhibitor 8 (1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one) or 9 ([4-(2-chloro-4a,10a-dihydro-phenoxazin-10-yl)-butyl]-diethyl-amine hydrochloride). Importantly, the enhancement of chloroquine analogs 5 on cell killing by Akt inhibitors 8 and 9 was cancer-specific. Thus, this combinational approach is highly promising in controlling tumors with a minimum side effect. Structural analysis of effective and ineffective chloroquine analogs suggests that the 4-aminoquinoline scaffold and lateral side chain of dimethylamino functionality play an important role for the enhancement of cell killing by Akt inhibitors.

PMID: 19945197 [PubMed - as supplied by publisher]




Anticancer Drugs. 2009 Sep;20(8):736-45.
Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells.

Rahim R, Strobl JS.
Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA.
The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have potential applications in cancer treatment. The growth of MCF-7 and MDA-MB-231 human breast cancer cells in vitro was inhibited by CQ and HCQ and these cells were more sensitive than nontumorigenic MCF-10A breast epithelial cells. Furthermore, all-trans retinoic acid (ATRA) augmented the anticancer effects of CQ and HCQ as evidenced by significant reductions in Ki67-positive cancer cells and clonogenicity compared with cells treated with CQ or HCQ in the absence of ATRA. As an earlier study suggested that CQ, HCQ, and ATRA are breast cancer cell differentiation agents, these agents were screened in cell-free histone deacetylase (HDAC) and histone acetyltransferase (HAT) assays. ATRA, but not CQ or HCQ, inhibited HDAC activity in HeLa nuclear extracts. Growth inhibitory concentrations of HCQ and ATRA stimulated purified p300/CBP-associated factor, where CBP is the cAMP-response element binding protein, HAT activity. To investigate whether growth inhibitory concentrations of these agents influenced protein acetylation in cells, gel-purified histone H3 and histone H4 were analyzed using mass spectrometry. HCQ alone and HCQ+ATRA treatments altered the acetylation status in the N-terminal lysines of histones H3 and H4 compared with dimethyl sulfoxide (DMSO) controls. The results indicated that HCQ and ATRA regulate protein acetylation events in MCF-7 breast cancer cells, and identify a potential mechanism for their effects on breast cancer cell growth and differentiation.

PMID: 19584707 [PubMed - indexed for MEDLINE]




Wikipedia: http://en.wikipedia.org/wiki/Chloroquine

Antitumor

The mechanisms behind the effects of chloroquine on cancer are currently being investigated. The best-known effects (investigated in clinical and pre-clinical studies) include radiosensitising effects through lysosome permeabilisation, and chemosensitising effects through inhibition of drug efflux pumps (ATP-binding cassette transporters) or other mechanisms.

Adverse effects

At the doses used for prevention of malaria, side-effects include gastrointestinal problems such as stomach ache, itch, headache, and blurred vision.
Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever, its severity correlated to the malaria parasite load in blood. There is evidence that it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.[7]
When doses are extended over a number of months, it is important to watch out for a slow onset of "changes in moods" (i.e., depression, anxiety). These may be more pronounced with higher doses used for treatment. Chloroquine tablets have an unpleasant metallic taste.
A serious side-effect is also a rare toxicity in the eye (generally with chronic use), and requires regular monitoring even when symptom-free.[8]
The daily safe maximum doses for eye toxicity can be computed from one's height and weight using this calculator.[9] The use of Chloroquine has also been associated with the development of Central Serous Retinopathy.
Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut, and death often occurs within 2½ hours of taking the drug. The therapeutic index for chloroquine is small, and just doubling the normal dose of chloroquine can be fatal.[10]

According to the PloS One Journal and cited by Scientific American, an overuse of Chloroquine treatment has led to the development of a specific strain of E. coli that is now resistant to the powerful antibiotic Ciprofloxacin [11]


Oral Chloroquine prescription info:

http://www.medicinenet.com/chloroquine-oral/article.htm


http://www.sciencedaily.com/releases...1220172131.htm
The drug, chloroquine, which has been in use since 1946, prevented development of cancer in models of two distinct human cancer syndromes, Burkitt lymphoma, a cancer of the lymphatic system, and ataxia telangiectasia (A-T), a rare and progressive immunodeficiency disease that predisposes patients to cancer, especially lymphoma and leukemia.
"Our study shows that chloroquine inhibits the final steps of a pathway that is required for tumor cell survival and effectively eliminates cancer cells in mouse models that replicate human tumors," said John Cleveland, a Scripps Research scientist who is chair of the Department of Cancer Biology at the institute's Jupiter, Florida, campus. "The fact that the drug attacks premalignant cells, and cells that overexpress transcription factor MYC, a notorious contributor to tumorigenesis that is implicated in more than 70 percent of all cancers, makes the use of this drug very attractive for chemoprevention and cancer treatment."
In the study, chloroquine was very effective in delaying the onset of spontaneous tumors in mice lacking ATM. The ATM gene is akey arbiter of the DNA damage response pathway and is mutated in patients with the cancer-inducing disorder ataxia telangiectasia. These malignancies are particularly difficult to treat because of the acute sensitivities of A-T patients to cytotoxic agents. Chloroquine now offers a potentially novel treatment for these patients because the drug preferentially eliminates cancer cells and is relatively well tolerated.
In addition, the scientists found that treating mouse models of human Burkitt lymphoma just once every five days also dramatically reduced lymphoma development. Interestingly, an epidemiologic study completed in the 1980s supports the potential of this treatment in humans. While this study was designed to investigate the link between malaria and the high incidence of Burkitt lymphoma in equatorial Africa, researchers found that chloroquine treatment decreased the incidence of lymphoma in the region by about 75 percent.



Are Dead Cancer Cells Feeding Cancer's Spread? (TLR9)

http://www.newswise.com/articles/are...tudy-the-issue

“What if by killing cancer cells with chemotherapy we inadvertently induce DNA structures that make surviving cancers cells more invasive? The idea is tough to stomach,” Selander says. “Fundamentally this question must be answered to advance the knowledge base and to know all the risks and benefits of cancer treatment.

Quote:
The pathway activated by the dead cancer cells is mediated in the body as a protein called toll-like receptor 9, or TLR9. This protein is present in the immune system and in many types of cancer. If TLR9 boosts metastasis, then researchers will work on finding targeted therapies that block or regulate this molecular pathway, Selander says.
Am J Physiol Renal Physiol. 2008 May;294(5):F1050-8. Epub 2008 Feb 27.
Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury.

Yasuda H, Leelahavanichkul A, Tsunoda S, Dear JW, Takahashi Y, Ito S, Hu X, Zhou H, Doi K, Childs R, Klinman DM, Yuen PS, Star RA.



Abstract

Mortality from sepsis has remained high despite recent advances in supportive and targeted therapies. Toll-like receptors (TLRs) sense bacterial products and stimulate pathogenic innate immune responses. Chloroquine, an inhibitor of endocytic TLRs (TLR3, 7, 8, 9), improves sepsis-induced mortality and AKI in a clinically relevant polymicrobial sepsis mouse model, even when administered 6 h after the septic insult. Mice deficient in the common adapter protein MyD88, downstream from most TLRs, have reduced mortality and acute kidney injury (AKI) from polymicrobial sepsis. However, the identity of the TLR(s) responsible for the host response to polymicrobial sepsis is unknown. Here, we show that Chloroquine administration attenuated the decline in renal function, splenic apoptosis, serum markers of damage to other organs, and prototypical serum pro- and anti-inflammatory cytokines TNF-alpha and IL-10. An oligodeoxynucleotide inhibitor (H154) of TLR9 and TLR9-deficient mice mirror the actions of chloroquine in all functional parameters that we tested. In addition, chloroquine decreased TLR9 protein abundance in spleen, further suggesting that TLR9 signaling may be a major target for the protective actions of chloroquine. Our findings indicate that chloroquine improves survival by inhibiting multiple pathways leading to polymicrobial sepsis and that chloroquine and TLR9 inhibitors represent viable broad-spectrum and targeted therapeutic strategies, respectively, that are promising candidates for further clinical development.

PMID: 18305095 [PubMed - indexed for MEDLINE]PMCID: PMC2386262Free PMC Article
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Old 08-22-2010, 10:53 AM   #2
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Re: Chloroquine (s)

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