Chemotherapy

Cancer is a leading cause of death in the U.S and across the world, with estimates indicating 17 million new cancer cases in 2018, 9.5 million of which resulted in death. Statistics show that in the past 20 years cancer death rates have decreased 27% due to emerging therapies. The use of chemotherapies to kill fast-growing cells in the body has become one of the most common cancer treatments in the world today. Chemotherapy-Induced Peripheral Neuropathies (CIPNs) are the most common side effects caused by chemotherapeutic agents. CIPNs have a prevalence of up to 85% in cancer patients undergoing chemotherapy. CIPNs triggered by chemotherapeutic drug use severely damage nerves branching from either the brain or spinal cord, initiating the development of acute and/or chronic symptoms. Platinum-based and taxane-based chemotherapeutics are among the most potent and versatile drugs available for combating cancer. The two of these drugs, carboplatin and docetaxel, are known to cause peripheral neuropathies and central neurotoxicity and were the focus of this project.

There has been substantial progress in cancer research that has markedly enhanced patient outcomes. However, chemotherapy resistance persists and often leads to multidrug resistance, rendering cancer cells unresponsive to multiple chemotherapy drugs, presenting a significant challenge in the effective treatment of the disease. Dysregulation in gene expression patterns caused by abnormalities in epigenetic mechanisms have been identified as contributing factors to the development and progression of cancer. Epigenetic research offers potential to discover drugs that target specific epigenetic modifications to regulate gene expression patterns in the context of chemotherapy resistance. I hypothesize that histone modifications on histone H3 and histone H4 contribute to doxorubicin resistance. The data presented here provides an initial screening of the mutant monoallelic histone yeast strains to identify post-translationally modifiable amino acids in H3 and H4 that could contribute to doxorubicin resistance. The possible targets of histone modifications were then repeated in triplicate to obtain statistical significance. Finally, Western blot techniques were used to identify the modification occurring on the histone H3 and histone H4 amino acid sites that were previously identified to be statistically significant.

Prostate cancer is one of the leading causes of death in men aged 40-55. Genistein isoflavone (4', 5', 7-trihydroxyisoflavone) is a dietary phytochemical with demonstrated anti-tumor activities in a variety of cancers. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy drug, primarily used for secondary treatment of ovarian,cervical and small cell lung cancers. This study was to demonstrate the potential anticancer activities and synergy of topotecan-genistein combination in LNCaP prostate cancer cells. The potential efficacy and mechanism of topotecan/genistein-induced cell death was investigated... Results: The overall data indicated that i) both genistein and topotecan induce cellular death in LNCaP cells, ii) topotecan-genistein combination was significantly more efficacious in reducing LNCaP cell viabiligy compared to either genistein or topotecan alone, iii) in all cases, cell death was primarily through apoptosis, via the activation of the intrinsic pathway, iv) ROS levels were increased and VEGF expression was diminished significantly with the topotecan-genistein combination treatment, v) genetic analysis of topotecan-genistein treatment groups showed changes in genetic expression levels in pathway specific apoptotic genes.... Conclusion: Treatments involving topotecan-genistein combination may prove to be an attractive alternative phytotherapy of adjuvant therapy for prostate cancer.

Alzheimer's disease (AD) is an increasingly common neurological disorder that mainly affects memory formation and retention. It is characterized by unique intercellular neurofibrillary tangles and extracellular beta-amyloid plaques. Histone deacetylase inhibitors (HDACi's) are competitive antagonists against histone deacetylases, causing histone acetyltransferases to acetylate the genome unregulated. This thesis investigates the use of new histone deacetylase inhibitors on recovering memory in a mouse model of Alzheimer's disease. By use of a fear conditioning paradigm, we have shown that these HDACI's increase memory in AD mice, but show either no effect or a positive effect in wild-type mice. Future experiments will investigate the efficacy of compound 966 and the spine density of hippocampal brain slices after fear conditioning trials.

Anticancer drugs, including nocodazole and vinblastine, work by disrupting the dynamics of microtubules. Unfortunately, these drugs often produce numerous side effects, including nausea, vomiting, loss of appetite, loss of hair, increased chance of infection, and fatigue. My thesis research evaluated the efficacy of using repeated low doses of microtubule drugs instead of a single high dose, in an attempt to minimize side effects. Using nocodazole and vinblastine, I first established the minimum effective concentration that disrupts the microtubules in normal human cells grown in vitro and treated cells with those concentrations over a period of several days. I found that microtubules were increasingly depolymerized as the days progressed. Next, I tested a combination of nocodazole and vinblastine at low concentrations.