Elucidation of Mechanism of Action of Novel Capsazepine Analog, CIDD-000099

Date

2020

Authors

Zboril, Emily Kate

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Volume Title

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Abstract

Oral cancer patients generally have a poor prognosis, with only about 60% of patients surviving 5-years after diagnosis. Treatments for oral cancer have many adverse side effects and further studies must be done to develop drugs that are more efficacious and result in fewer side effects. To achieve this, CIDD-000099 was developed by the laboratory of Dr. Cara Gonzales DDS, PhD at the UT Health Dental School along with the Center for Innovative Drug Discovery at The University of Texas at San Antonio based on the vanilloid molecule, capsazepine. CIDD-000099 has been shown to produce cytotoxic effects in multiple cancer cell lines, including oral squamous cell carcinoma (OSCC). The present study sought to evaluate the nature of that cytotoxicity and further elucidate its mechanism of action. The results show that CIDD-000099 is able to reduce cell viability in OSCC cell lines Cal27 and HSC-3 in both a dose- and time-dependent manner. Furthermore, investigation of Bcl-family proteins and the cleavage of PARP showed that cancer cells treated with this drug undergo apoptosis. We hypothesized that this could be due to either i) inhibition of mitochondrial function, or ii) induction of ER stress. We determined that in cells treated with CIDD-000099, both complex II of electron transport and ATP synthase (complex V), which is involved in oxidative phosphorylation and ATP generation, are inhibited. Moreover, the results also showed an increase in ER stress markers and an inability of treated cells to achieve calcium homeostasis following exhaustion of calcium stores. While we have established that both ER stress and mitochondrial dysfunction are part of the cellular response to CIDD-000099, further studies will need to be done to determine if one initiates or potentiates the other.

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Keywords

Calcium Signaling, Mytochondrial Dysfunction, Novel Drug, Oral Cancer, Oral Squamous Cell Carcinoma

Citation

Department

Integrative Biology