published_or_final_version / Anatomy / Master / Master of Philosophy

Indiana University-Purdue University Indianapolis (IUPUI) / Resveratrol has been shown to inhibit cell growth and induce apoptosis, as well as augment chemotherapeutics and irradiation in multiple cancer types. However, it is unknown if resveratrol is beneficial for treating drug-resistant cancer cells. To study the effects of resveratrol in triple negative breast cancer cells that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the MDA-MB-231 breast cancer cell line. The resulting cell line, MDA-MB-231/PacR, exhibited a 12-fold increased resistance to paclitaxel but remained sensitive to resveratrol treatment. Resveratrol treatment reduced cell proliferation and colony formation and increased senescence and apoptosis in both the parental MDA-MB-231 and MDA-MB-231/PacR cell lines. Importantly, resveratrol treatment augments the effects of paclitaxel in both cell lines. The expression of the drug efflux transporter gene, MDR1, and the main metabolizing enzyme of paclitaxel gene, CYP2C8, was increased in the resistant cells. Moreover, pharmacological inhibition of the protein products of these genes, P-glycoprotein and CYP2C8, decreased paclitaxel resistance in the resistant but not in the parental cells, which suggests that the increase of these proteins are important contributors to the resistance of these cells. In conclusion, these studies imply that resveratrol, both alone and in combination with paclitaxel, may be useful in the treatment of paclitaxel-sensitive and paclitaxel-resistant triple negative breast cancers.