Date of Award

2019

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Piyali Dasgupta,Committee Chairperson

Second Advisor

Dr. Monica Valentovic

Third Advisor

Dr. Gary Rankin

Fourth Advisor

Dr. Richard Egleton

Fifth Advisor

Dr. Travis Salisbury

Abstract

Lung cancer continues to be the leading cause of cancer related mortality worldwide. Lung cancer is not a single disease but an umbrella that encompasses two major classifications, nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). SCLC represents about 15- 20% of all lung cancer cases and is almost exclusively diagnosed in smokers. Typically, patients will respond very well to first line treatment, but face inevitable relapse. The fact that SCLC still carries a grim 5-year survival rate of less than 5% highlights the lack of advancement in treatment options to effectively improve patient response and survival. Capsaicinoids, in particular Capsaicin (the spicy compound in chili peppers), have previously been reported to be an advantageous adjunct treatment with traditional chemotherapeutic options in several cancer types. One challenge to the use of capsaicin is the variety of side effects, such as gastrointestinal pain, sweating and ulcers that are frequently reported with clinical administration. Synthetic nonpungent capsaicinoids, which show many of the same bioactive properties as capsaicin may, however, be a promising alternative. The studies in this dissertation investigated the use of capsaicin and several non-pungent analogs as chemotoxic or adjuvant therapy for SCLC. Utilizing various in vitro and in vivo models we investigated the synergistic effects of capsaicin and camptothecin. We provide new evidence that capsaicin synergistically sensitizes SCLC to the effects of camptothecin, inducing a rise in intracellular calcium levels and activating the calpain pathway to induce apoptosis. Analysis of the antineoplastic capacity of various capsaicinoid analogs found arvanil to be the most potent capsaicinoid at inducing apoptosis in SCLC cell lines. Similar to capsaicin, arvanil also induced apoptosis in SCLC cell lines by raising intracellular calcium levels leading to increased calpain activity. The chemotoxic potency and non-pungent character of arvanil supports the future investigation of the adjuvant use of arvanil with camptothecin or other chemotherapeutic agents to find a combination therapy that provides the same synergistic effects as capsaicin, while lacking the adverse side effect profile. Taken together, these studies demonstrate that capsaicin and arvanil have the potential to successfully treat SCLC in combination with conventional chemotherapeutics, as well as possibly treating other cancer types.

Subject(s)

Lungs -- Cancer -- Research.

Lungs -- Cancer -- Treatment.

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