Loading...

Investigation of Anticancer Drug Metabolism in Saccharomyces Cerevisiae as a Drug Resistance Model

Hamed Rahimi, Reza | 2023

60 Viewed
  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 56483 (06)
  4. University: Sharif University of Technology
  5. Department: Chemical and Petroleum Engineering
  6. Advisor(s): Yaghmaei, Soheila; Sardari, Soroush
  7. Abstract:
  8. Cancer is a life-threatening group of diseases that arises from the uncontrolled growth and division of cells in the body. Treatment options for cancer include surgery, chemotherapy, radiation therapy, immunotherapy, targeted therapy, and hormone therapy. However, resistance to anticancer drugs can develop through a variety of mechanisms, such as the upregulation of drug efflux pumps and alterations in DNA repair mechanisms. One common mechanism of drug resistance is through changes in metabolism, where cancer cells switch to alternative metabolic pathways to survive and evade the effects of anticancer drugs. The development of new drugs targeting specific molecules and pathways involved in cancer growth and spread is necessary to overcome drug resistance and improve treatment outcomes. This study focused on identifying the cancer type, anticancer drug, and associated resistant metabolic pathway. Ovarian cancer, cisplatin, and Glutaminolysis were selected as the specific components for investigation. The research involved the examination of various cancer models to establish a foundation for both experimental and computational analysis. Through a combination of numerical and computational methods, we initially simulated the metabolic processes of Saccharomyces cerevisiae as a representative model for ovarian cancer. The analysis revealed a striking 77 percent metabolic similarity. Through metabolic manipulation analysis, by hypothetically reducing the current glutamate concentration by 90 percent, our projections indicated a 25 percent decrease in the levels of critical metabolites, including succinate, fumarate, malate, and citrate, essential for the growth and proliferation of drug-resistant cancer cells. Transitioning from computational analysis to experimental work, we successfully generated a cisplatin-resistant strain of Saccharomyces cerevisiae over several months, resulting in a significant fourfold increase in the minimum cisplatin concentration required to inhibit the growth of these resilient cells. However, the most promising breakthrough emerged when we introduced glutaminase inhibitors into the equation. Our data strongly suggested that incorporating glutaminase inhibitors could effectively mitigate drug resistance. Putting theory into practice, we harnessed the EGCG compound from green tea and employed it as a glutaminase inhibitor to combat cisplatin resistance in Saccharomyces cerevisiae. Our rigorous assessments unequivocally demonstrated the remarkable efficacy of EGCG in treating cisplatin-resistant cells, nearly restoring their sensitivity to the drug. These compelling results provide a solid foundation for future research endeavors, including potential in-vitro testing with actual ovarian cancer cells exhibiting drug resistance
  9. Keywords:
  10. Saccharomyces Cerevisiae ; Cisplatin ; Drug Resistance ; Anticancer Drugs ; Metabolic Manipulation ; Epigallocatechin Gallate (EGCG)

 Digital Object List

 Bookmark

No TOC