Investigating the anticancer potential of phytochemicals from the diverse flora of Indian sub-continent has been one of the major research interests of our group. We have reported the pro-apoptotic effects of curcumin (from Curcuma longa), allicin, emodin and resveratrol in various cell lines, with reference to their influence on intracellular signaling intermediates like NF-κB, Bcl-XL, Bax, caspases and heat shock proteins. The questions I am addressing include: What makes cancer cells differentially susceptible to different pro-apoptotic phytochemicals? Which are the other novel players in the signal transduction pathways influenced by different phytochemicals? How can these studies be extended for developing useful anticancer drugs? Extension of these studies into in vivo models would give useful insights into the aspects of pharmacological dosages, treatment parameters and the use of combination chemotherapy.

Cervical cancer is the most common gynecological malignancy affecting women in developing countries. NF-κB, a ubiquitous transcription factor has been found to be deregulated in tumors of different tissue origin and cell lines. Previous studies from our lab showed that NF-κB was constitutively activated in cervical tumors. The aim of my study is to identify the cause of activation of NF-κ B in cervical cancer and its target genes that help in tumor initiation, progression, tissue invasion and metastasis. The transcription factor NF-κB has been shown to confer on tumor cells the ability to evade programmed cell death (Apoptosis). Since it is an important factor that helps in tumor cell survival it is a crucial target for therapeutic intervention in anticancer therapy. The mechanism of NF-κB regulation is complex and since it is also involved in immune regulation, inflammation and auto immune diseases it is an area of paramount importance with respect to therapeutics.

The development of malignant tumors results from deregulated proliferation or an inability of cells to undergo apoptotic cell death. Hence the anticancer therapeutics is targeted to inhibit proliferation and induce apoptosis in sensitive tumor cells. But the therapy fails in some tumors subsequent to an inherent ability of accelerated activation of survival responses. During the development and progression of solid tumors, the tumors are subjected to hypoxic and nutrient depleted environments. The development of chronic and fluctuating hypoxic regions in tumors has profound consequences for malignant progression, response to therapy and overall patient survival. Understanding the events involved in hypoxia tolerance will offer new opportunities for antitumor modalities. These hypoxic and other cellular perturbations lead to ER stress responses. Tumor cells try to overcome these stress by turning up ER stress mediated survival responses. But if the ER stress is too excessive or prolonged it leads to ER stress induced apoptosis. Currently work is progressing to understand the molecular link between survival and death in ER stress with special emphasize on different caspase and their regulators.

All normal cells are mortal and prone to senescence as Telomerase is repressed and telomeres get shorten progressively with cell division. However almost all cancer cells are immortal and express telomerase. Ectopic expression of hTERT, catalytic subunit of telomerase in normal human somatic cell leads to cell immortalization by maintaining telomere length, hence provides survival advantages to the cell. However the molecular mechanism of apoptosis resistance and the interacting partners of h TERT in apoptosis resistance is still not clear. We are going to study and navigate into this unknown mechanism with the help of hTERT immortalized cells, their normal counterparts and cancer cells. Apart from that, also we are trying to look out the signaling pathway taking place during the induction of apoptosis in the absence of proapoptotic molecules Bak and Bax which are shown to be essential for stimulating the mitoapoptotic pathway by releasing cytochrome c from mitochondria.

Certain tumor cells develop resistance to apoptosis, which enhances spontaneous growth of tumors and renders them resistant to host defence mechanism, chemotherapy and radiotherapy. Over expression of some antiapoptotic proteins like Bcl 2, Bcl XL, Heat shock proteins like HSP 70, 90, 27 etc are capable of preventing cell death induced by anti cancer drugs leading to drug failure. Recently we have shown that antisense down regulation of Bcl XL or HSP 70 can sensitize chemoresistant cancer cells to drugs suggesting silencing of antiapoptotic proteins as better therapeutic targets for bypassing chemoresistance. So small molecule inhibitors of such proteins could in theory is a panacea for the systemic treatment of chemoresitant tumors. Numerous natural and synthetic heat shock protein inhibitors have been developed in recent years. It is proposed to evaluate the potential of certain small molecular inhibitors of heat shock proteins like Geldanamycin,17 AAG, Radicicol, Novobiocin in combination with plant derived anticancer agents like Reserveratrol / Quercetin to sensitive chemoresistant cancer cell lines over expressing different HSPs and Bcl2 / BclXL.

Human solid tumours often possess a hypoxic microenvironment. Hypoxic tumour cells are known to contribute to radioresistance, chemoresistance and increased metastasis. Many studies have shown cancer stem cells (CSC) or tumour-initiating cells (TIC) also to be therapy-resistant both in vitro and in vivo, resulting in tumour relapse and metastases. Although much work have been done on tumour hypoxia and the expression of various hypoxia inducible genes via mediation of HIF-1, little information is known about the influence of hypoxia on tumour initiating cells. My study is aimed at identifying the molecular events operating in TICs as a result of hypoxia, culminating in therapy resistance. My collaborator in this study is Dr. K. Ramdas (Head and Neck Speciality Clinic) from Regional Cancer Center Thiruvananthapuram.