Autophagy And Senescence In Cancer Therapy PDF Download

While current treatments in cancer, such as chemotherapy and radiation, can generally be effective in eliminating disease in patients, there also exists the possibility of recurrence of cancer cells over time. In patients diagnosed with locally advanced head and neck carcinoma, about 50-60% develop a loco-regional recurrence within two years, and 20-30% of patients develop metastatic disease at distant sites in the body [5]. On a cellular level, one mechanism for this survival may be that natural mechanisms such as autophagy and senescence play a role in allowing cells to survive after undergoing treatment. One standard of care chemotherapy for head and neck cancer is cisplatin, which was used as the primary treatment in this project. HN12 cells (head and neck tumor cells; p53-null) showed significant growth arrest and decreased viability in response to 5 [mu]M cisplatin treatment, but proliferative recovery over time. It was found that apoptosis did not play a significant role in this growth arrest, as assessed by annexin V/propidium iodide assays to measure apoptotic cell death. Additionally, cisplatin was shown to induce significant levels of autophagy in head and neck tumor cells with acridine orange staining and western blot analysis; however, pharmacological inhibition of autophagy with either chloroquine (5 [mu]M), bafilomycin (5 nM), or 3-methyladenine (1 mM) did not sensitize cells to treatment with cisplatin, indicating a nonprotective role of autophagy. Additionally, HN12 cells showed significant levels of senescence, a form of cellular growth arrest, as indicated by beta-galactosidase upregulation, flattened morphology, and cell cycle arrest. Targeting of senescent cells with the senolytic ABT-263, a Bcl-2/Bcl-xl inhibitor, was effective in sensitizing cells to treatment with cisplatin, but cellular proliferation still occurred over time. Additionally, the HN30 cell line (p53 wild type) was compared to the HN12 line and experiments suggested that p53 status did not play a significant role in induction of autophagy or the sensitization to the senolytic, although more work needs to be done. Overall, these studies provide evidence that autophagy is nonprotective in the HN12 cell line in response to cisplatin treatment, and that senescence plays a role in allowing cells to survive over time. Further, ABT-263 is effective in targeting the remaining population of senescent cells after cisplatin treatment and may be a potential therapeutic mechanism in preventing the recurrence of head and neck cancers.