Drug Resistance in Cancer
Drug Resistance in Cancer:
Cancer cell resistance to a wide spectrum of anticancer drugs continues to be a major concern for effective treatment. Many different mechanisms have been suggested to explain the development of multidrug resistant (MDR) phenotype in cancer cells. One of the mechanisms by which tumors acquire drug resistance is the over expression of membrane transporters such as drug efflux pump P-glycoprotein (P-gp/ABCB1) which transports structurally and functionally unrelated compounds. Over the past two decades, a number of chemical entities have been investigated in order to reverse P-gp mediated MDR in cancer cells. Some have undergone clinical trials, but currently none are in clinical use. The main problem for the development MDR inhibitors seems due to poor specificity, low affinity for the binding site, interference with the physiological role of P-gp and sister proteins, and, last but not least, interference with the pharmacokinetics of the associated chemotherapy. Nitric oxide (NO) is a signaling molecule involved in the control of cellular growth, differentiation and apoptosis It has been demonstrated that Statins enhance the transcription of (iNOS). Nitric oxide production is quite different in doxorubicin resistant and sensitive cells; restoration of NO production in resistant cells could reverse the MDR in cancer. Our research aim is to develop new types of NO-releasing hybrid compounds to obtain a tissue-specific NO-related function. These new molecules supplement NO exogenously when the body cannot generate sufficient amounts to allow normal biological functions.
Recent Research Highlights:
In recent times numerous major interests combined into a novel concept of cancer drug resistance. Resistance to several anticancer drugs has been associated with increased efflux of a drug out of the cell, the so-called multidrug-resistance (MDR). This efflux is energy dependent and hence requires ATP. One of these pumps, ABCG2, initially called Breast Cancer Resistance Protein (BCRP), was associated with resistance to drugs such as doxorubicin and Mitoxantrone. Rajendra Prasad, Mayur YC and Deepak Reddy G demonstrated that various N10-substituted acridones have ability to revert doxorubicin resistance in different cancer cells and also shown significant cytotoxic property. Further, mechanistic studies suggest that acridone derivatives interact with DNA duplex by intercalation, possesses higher affinity to GC than AT base pairs of the DNA and they could not interact non-covalently with the minor grooves of the DNA in solution free gas phase. It indicates that the cytotoxic affects of acridone derivatives by intercalating only with major grooves of the DNA. Studies also shown that mode of inhibition of Calmodulin by inhibiting the Ca2+/Calmodulin stimulated cAMP- Phosphodiesterase activity and have no direct effects on the enzyme itself.
As a sequel in our research to discover new MDR modulators, Rajendra Prasad and GJ Peters have designed various molecules by introduction of a NO donating group into a P-gp and/or BCRP inhibitor acridone carboxamide moiety would be capable to release NO in a controlled manner and might reverse the doxorubicin resistance in cancer. Newly developed nitric oxide donating acridone carboxamides were shown significant activity against drug sensitive and resistant cell lines and also reverse MDR, which might be related the nitric oxide release rate. The results from the cytotoxicity assays, in-vitro nitrite release, and drug accumulation studies clearly indicate that NO donating acridones had a remarkable rate of nitrite release and cytotoxic effects. Moreover, studies also demonstrated that exogenous release of nitric oxide by NO donating acridones enhanced the accumulation of doxorubicin in MCF7/Dx cell lines when it is co-administered with doxorubicin by inhibiting efflux process. It was also clear that presence of NO group potentiated the cytotoxic effect of the acridone derivatives. Further, nitric oxide donating group could potentiate the N10-substituted acridones to reverse the doxorubicin resistance in MCF7/Dx cells. Current research therefore focuses on the critical role of nitric oxide on efflux pumps and reversing drug resistance in cancer.