Text

theses

In this dissertation, I have evaluated the role of heat (physical) stress in cell death. It has been previously reported that heat shock causes cancer cell death and is currently used as an adjuvant therapy in cancer treatment (Wust 2002). However, heat therapy is currently limited due to the requirement of high temperatures (45°C) for physiological effect. Improved efficacy of treatment could be achieved by understanding the mechanism of heat shock induced tumor cell death which is not well understood. A possible mechanism for heat induced tumor cell death could involve activation of proteases by heat which degrades key survival proteins thus leading to loss of viability. It has been previously reported that heat shock induced tumor cell death is associated with loss of eIF5A, a highly conserved survival protein (Takeuchi 2002, Gosslau 2009). I have independently reconfirmed the results of these studies and further evaluated the role of two protease inhibitors. The findings suggest the possibility that various proteases get activated by heat shock and multiple proteins, including eIF5A get degraded eventually leading to loss of viability. The findings of this dissertation strengthen the hypothesis that proteases are involved in heat induced tumor cell death and use of small molecule activators of proteases could possibly improve the efficacy of heat-treatment through synergistic/additive mechanism. I studied the effect of resveratrol ((3,5,4'-trihydroxy-trans-stilbene) and its analogs, MR-4 (3,4,5,4’-tetramethoxy-trans-stilbene) and MC-4 (3,4,5,4’-tetramethoxy-cis-stilbene) in inflammation, neuroblastoma differentiation and preadipocyte differentiation where resveratrol has been reported to be involved. In this dissertation, I have successfully established the effect of MC4 and MR4 in inflammation, neuroblastoma and adipogenesis disease models. The mechanism of action for these biomolecules remains to be evaluated but it can be speculated that AMPK is a potential upstream target of resveratrol, MC4 and MR4, given that AMPK is known to play a role inflammation, neuroblastoma differentiation and adipogenesis. Both MC4 and MR4 offer the advantage of improved bioavailability and lower dosage to achieve the same physiological effect as resveratrol making them an attractive target for therapeutics in inflammation, neuroblastoma and adipogenesis.

ETD_5271

Ph.D.

Includes bibliographical references

by Priti S Tiwari

doi:10.7282/T32F7KHM

ETD doctoral

The author owns the copyright to this work.