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Spicing up Chemotherapy

We have previously reported on curcumin, the principal active ingredient of turmeric, which has been claimed to have activity against a variety of conditions. Now scientists at Wayne State University have explored the activity of curcumin against cancer stem cells (CSCs).

Colorectal cancer is the third most common form of cancer and, despite aggressive surgical intervention and chemotherapy, almost 50% of patients develop recurrent disease. In epithelial cancers, including colorectal cancer, growing evidence supports the hypothesis that tumour initiation and maintenance is driven by CSCs. Consequently, it is believed that failure to eliminate the underlying CSC population is responsible for cancer recurrence following therapy.

Curcumin (keto form)

Curcumin (keto form)

Curcumin has already been shown to have efficacy against a number of tumours in both animal models and early clinical trials. This latest study explored the activity of curcumin on colon cancer derived CSCs, either alone or in combination with the current standard treatment, FOLFOX (5-fluorouracil (5-FU) plus oxaliplatin). In cell culture experiments the researchers demonstrated that FOLFOX treatment increased the percentage of CSCs, presumably due to CSC-sparing. Treatment of these FOLFOX-surviving cells with curcumin alone or in combination with FOLFOX resulted in a marked reduction in the CSC population.

The study, published in Translational Oncology, went on to examine the potential mechanisms for the observed effects. The authors suggest that curcumin may represent a viable adjunct to current chemotherapy of colorectal cancer that could reduce rates of recurrence.

Integrin Inhibitors Can Boost Rather than Block Tumour Cell Growth

tumour angiogenesisTo grow beyond a certain size, solid tumours need to secure an adequate blood supply and are able to induce angiogenesis to achieve this. Many modulators of angiogenesis have been identified including growth factors such as vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), integrin and cadherin adhesion molecules, and matrix-degrading enzymes. Although angiogenesis inhibitors that target the VEGF pathway such as bevacizumab (Avastin™) and sunitinib (Sutent™) have shown good results in some patients, trials of integrin inhibitors have generally proved less successful.

cilengitide structureIntegrins are cell surface receptors that play a role in defining cell shape, attachment, and mobility as well as in signal transduction and regulation of the cell cycle. Research funded by Cancer Research UK now suggests that the lack of clinical efficacy of integrin inhibitors may be due to insufficient levels of drug in the body. In laboratory studies, low levels of the experimental integrin inhibitor, cilengitide, were found to boost rather than block tumour cell growth. Cilengitide is a cyclic Arg-Gly-Asp peptide which, at higher doses, binds to and inhibits the activities of the αvβ3 and αvβ5 integrins, thereby inhibiting endothelial cell-cell interactions, endothelial cell-matrix interactions, and angiogenesis. The research, which is published in the journal Nature Medicine, found that low (nM) doses of cilengitide stimulated the supply of blood to the tumour and promoted its growth. Although very low doses of the drug did not have a direct effect on cancer cells, when they were grown alongside blood vessel cells low levels of cilengitide boosted growth of the cancer cells. Low concentrations of cilengitide were shown to promote VEGF-mediated angiogenesis by altering αvβ3 integrin and VEGFR2 trafficking, promoting endothelial cell migration to VEGF.

Even when high doses of cilengitide are administered to patients, blood levels fall in a few hours down to the levels that stimulated rather than blocked tumour growth, suggesting a reason for the poorer than expected efficacy in clinical trials. The study suggests that changing the route of administration or dosing schedule of integrin inhibitors may enhance their clinical efficacy.

Note added 25/3/09, 16.15: Merck Serono released a statement regarding media coverage on pre-clinical integrin inhibitor study in animal model, published in Nature Medicine (22nd March 2009), stating:

Isolated preclinical animal experiment findings do not reflect the actual clinical experience.

The press release can be seen here.

Green Tea Blocks Effectiveness of Cancer Drug

tea plantTea drinking is a tradition dating back thousands of years and green tea, particularly, is thought to have many health-giving properties. Green tea has also been investigated for possible use in the prevention or treatment of cancer, but a new study by researchers at the University of Southern California has shown that a component of green tea blocks the anti-tumour effect of the proteasome inhibitor, bortezomib (Velcade®), which is used to treat multiple myeloma. Before the study, the researchers believed that epigallocatechin gallate (EGCG), or other components of green tea, would enhance the effectiveness of bortezomib and were surprised to find the opposite effect.

bortezomibIn cell culture experiments, 10µM EGCG provided complete protection from the cytotoxic effects of 10nM bortezomib and 2.5µM EGCG also afforded significant (~80%) protection. In tumours from nude mice implanted subcutaneously with multiple myeloma cells, treatment with bortezomib alone (0.5mg/kg) caused a significant increase in apoptosis. In tumours from mice treated with bortezomib and EGCG (25 or 50mg/kg), however, there was no increase in apoptotic cell death when compared to tumours from untreated control mice.

epigallocatechin gallateThe authors showed that EGCG was exerting its inhibitory effect on the cytotoxicity of bortezomib by a direct covalent interaction between a 1,2-dihydroxybenzene group of EGCG with the boronic acid group of bortezomib, resulting in the formation of a cyclic boronate ester. EGCG also blocked the cytotoxicity of other boronic acid containing proteasome inhibitors, but had no effect on the cytotoxicity of structurally different proteasome inhibitors.

Because EGCG concentrations of 5-8µM can be achieved by consuming concentrated green tea extracts, the authors strongly advise that cancer patients receiving bortezomib therapy should avoid green tea products, especially the concentrated liquid or capsule forms. Studies show that green tea may improve the effectiveness of other cancer therapies.

The study is published in the February 3rd First Edition of the journal Blood.

Timing Could Be Critical In Chemotherapy

The circadian clock regulates a wide range of physiological activities and, for many years, it has been suggested that the time of day at which cancer patients receive chemotherapy or radiation therapy can influence both the effectiveness and side-effects of the treatment. A lack of understanding of the complex mechanisms underlying this effect – together with logistical considerations – has, however, prevented timing from becoming a major determinant in most treatment centres. A study from scientists at the University of North Carolina at Chapel Hill has now identified a biochemical mechanism which may explain circadian sensitivity to the anti-cancer drug cisplatin.

The results, published in the 21st January Early Edition of PNAS, suggest that treatment with chemotherapy may be most effective at times of the day when levels of one the DNA repair enzymes are at their lowest. xpa proteinThe enzyme is xeroderma pigmentosum A (XPA), the component of the nucleotide excision repair system that repairs bulky lesions in DNA such as those caused by cisplatin. The study showed that the activity of XPA in brain tissue from mice followed a circadian rhythm with peak levels some 5-10-fold higher than the lowest levels. It is not yet known whether the circadian levels of XPA in tumour cells or other cells of the body follow the same oscillations as those in the brain, but the study clearly suggests that circadian changes in levels of XPA should be taken into account when designing chemotherapy regimens. Studies on the effect of timing on treatment with cisplatin in rodents and human patients have so far focussed largely on reducing toxicity, and results are complicated by the fact that rodents are nocturnal. Cisplatin was generally found to be most toxic in both rodents and humans when administered soon after awakening.

The present study could also have implications for the prevention of cancer, for example by allowing people to use extra protection against the damaging effects of ultraviolet irradiation from the sun at those times of day when levels of DNA repair enzyme in the skin are at their lowest.

High Dose Vitamin C May Reduce Effectiveness of Chemotherapy

Vitamin CVitamin C is an essential nutrient that can be synthesised by most organisms, with humans being the most well-known exception. Although the health benefits of eating fruits and vegetables are well recognized, optimal daily intake of vitamin C is still the subject of much on-going debate.

A new study in leukemia and lymphoma cell lines has shown that pretreatment with vitamin C dose-dependently reduces the effectiveness of the widely used but mechanistically dissimilar cancer drugs, doxorubicin, cisplatin, vincristine, methotrexate, and imatinib. A similar effect was seen in mice with RL cell–derived xenogeneic tumours, when vitamin C significantly reduced the effectiveness of doxorubicin in preventing growth of the tumours. All of the drugs used in the study cause depolarization of the mitochondrial membrane in the tumour cells which leads to cell death. This mitochondrial damage was inhibited in the presence of vitamin C, and probably explains why the drugs were less effective.

Although this study suggests that use of vitamin C supplements during cancer treatment may limit the effectiveness of chemotherapy, it is difficult to know what dose of vitamin C would be detrimental in patients.

New Indications for AMD-3100



A drug which failed to reach the market as a treatment for HIV/AIDS has recently been shown to improve the survival of mice infected with West Nile virus, a virus that can cause encephalitis. It is believed that the drug, AMD-3100, acts by allowing T-cells to cross the blood-brain barrier and combat virus infecting the brain.

The drug works by blocking the receptor for the chemokine, CXCR4, and was originally developed to prevent the syncytium-forming variant of HIV using this receptor to gain entry to cells. Clinical trials, however, failed to show robust anti-viral activity.

The CXCR4 receptor and its physiological ligand, SDF-1, are also involved in mobilisation of hematopoietic stem cells into the bloodstream. Genzyme has recently filed applications in the US and Europe for AMD-3100 (Mozobil™, plerixafor) to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma. Because patients receive high-dose chemotherapy, which destroys bone marrow, a stem cell transplant is needed after chemotherapy to replenish blood-forming bone marrow cells. Genzyme has been developing Mozobil since its acquisition of AnorMED in 2006.