Chandra, Dhyan, PhD

Department of Pharmacology & Therapeutics
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY USA 14263
Telephone: 716-845-4882
FAX: 716-845-8857
e-mail: dhyan.chandra@roswellpark.org

Dr. Dhyan Chandra joined the staff of Roswell Park Cancer Institute in 2007. He earned his Doctoral degree in Biochemistry from the School of Life Sciences, Jawaharlal Nehru University, New Delhi, India. Prior to joining Roswell Park, Dr. Chandra was an Instructor in the Department of Carcinogenesis, Science Park-Research Division, University of Texas MD Anderson Cancer Center, Smithville, Texas.

Research Interests

Apoptosis signaling, oxidative stress, cancer stem cells, and anticancer therapeutics

Current Research

The primary focus of our research is to elucidate molecular mechanisms of cancer cell apoptosis. Apoptosis (also called programmed cell death) is the predominant form of cell death and plays a very important role in embryonic development and tissue homeostasis. Abnormal deficiency in apoptosis is hallmark of cancer and autoimmune diseases. Additionally, most anticancer therapeutics induces apoptosis to kill cancer cells by activation of caspases. The Apaf-1 apoptosome and death-inducing signaling complex (DISC) are the two main protein complexes to activate caspase-9 and caspase-8 respectively. These two initiator caspases (i.e., caspase-9 and -8) then activate effector caspases such as caspase-3 to execute the process of cell death.

Our immediate goal is to understand how cancer cells adopt various mechanisms to avert apoptosis for their long-term survival. Our findings along with others suggest that very early during apoptosis stimulation, cells mobilize various prosurvival mechanisms to deactivate pre-mitochondrial and mitochondrial apoptotic events. Later proapoptotic machinery predominates and prosurvival molecules become unable to protect mitochondrial integrity and leading to the release of cytochrome c. Most interestingly, we have recently provided evidence of the existence of survival mechanisms in the form of nucleotides even after cytochrome c is released. It turned out that nucleotides bind with cytochrome c, and therefore, do not allow cytochrome c to interact with Apaf-1 leading to inhibition of apoptosome formation, which ultimately blocks the caspase cascade. Altogether, our findings suggest that cancer cells must deplete the pools of nucleotides along with maximal cytochrome c release for optimal cell apoptosis. Various important questions remain unanswered, such as, how level of nucleotides is controlled, and how nucleotides regulate apoptosome formation and caspase activation. We are most specifically interested in investigating the molecular events involving apoptosome dysfunction in cancer cells. Similarly, cancer cells also adopt various approaches to inhibit proper DISC assembly, such as by upregulating levels of FLIP. We and others have shown that mitochondria play a very important role in regulating caspase activation initiated by DISC pathway. Therefore, studying how mitochondria regulate caspase activation in response to cancer therapeutics will significantly advance our understanding on apoptotic/survival pathways in cancer cells. Our ultimate goal is to identify and characterize the molecules that can activate/promote proper apoptosome/DISC assembly, which will be very significant in the development of anticancer therapeutics.

The current evidences suggest that present available anticancer therapeutics are unable to induce apoptosis in cancer stem cells and these rare cells are believed to be the initiating cells for tumor development. How cancer stem cells possess survival advantage is not clearly understood. Future research on apoptotic pathway in cancer stem cells will provide a very promising approach for more targeted cancer treatment. Using cellular, biochemical, and molecular biology approaches, we will expand our research to delineate apoptotic pathway in these rare cells. Our long-term goal is to develop anticancer regimen based on apoptosis signaling in cancer stem cells.

Selected Publications

1) Chandra, D., Bratton, S.B., Person, M.D., Tian, Y., Martin, A.G., Ayres, M., Fearnhead, H.W., Gandhi, V., and Tang, D.G. (2006) Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome c and inhibiting apoptosome. Cell, 125, 1333-1346.

2) Patrawala, L., Calhoun, T., Schneider-Broussard, R., Li, H., Bhatia, B., Tang, S., Reilly, J.G., Chandra, D., Zhou, J., Claypool, K., Coghlan, L., and Tang, D.G. (2006) Highly purified CD44⁺ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene, 25, 1696-708.

3) Chandra, D., Choy, G., Daniel, P.T., and Tang, D.G. (2005) Bax-dependent regulation of Bak by voltage-dependent anion channel 2. J. Biol. Chem., 280, 19051-61.

4) Liu, J.W., Chandra, D., Rudd, M.D., Butler, A.P., Pallotta, V., Brown, D., Coffer, P.J., and Tang D.G. (2005) Induction of prosurvival molecules by apoptotic stimuli: Involvement of FOXO3a and ROS and implications in cancer therapy. Oncogene, 24, 2020-2031.

5) Chandra, D., Choy, D., Deng, X.A., Bhatia, B., Daniel, P., and Tang, D.G. (2004). Association of active caspase-8 with the mitochondrial membrane during apoptosis: potential roles in cleaving BAP31 and caspase-3 and mediating mitochondria–ER crosstalk in etoposide-induced cell death. Molecular and Cellular Biology, 24, 6592-607.

6) Chandra, D. and Tang, D.G. (2003) Mitochondrially-localized active caspase-9 and caspase-3 resluts mostly from trnaslocation from cytosol and partly from caspase-mediated activation in the organelle- Lack of evidence for Apaf-1-mediated procaspase-9 activation in the mitochondria. Journal of Biological Chemistry, 278, 17408-17420.

7) Chandra, D., Liu, J-W., and Tang, D.G. (2002) Early mitochondrial activation and cytochrome c up-regulation during apoptosis. Journal of Biological Chemistry, 277, 50842-50854.

8) Liu, J-W., Chandra, D., Tang, S-H., Chopra, D., and Tang D. G. (2002) Identification and characterisation of Bimg, a novel proapoptotic BH3-only splice variant of Bim. Cancer Research, 62, 2976-2981.