The inhibitory effect of cisplatin, paclitaxel, and pemetrexed on the growth of PC9GR cells resistant to NK cell-mediated cytotoxicity during the COVID-19 pandemic.

Abstract

e15009 Background: Lung cancer patients have a significantly higher risk of contracting COVID-19, and interactions with the healthcare system during cancer therapy can put patients at risk. Preliminary studies in COVID-19 patients with severe disease found a reduction in the number and function of natural killer (NK) cells. Other studies in COVID-19 patients reported acute respiratory distress syndrome (ARDS) due to the extreme release of inflammatory cytokines. Besides, adverse effects of chemotherapy, such as chemotherapy resistance and the escalation of cellular senescence can worsen the condition of patients with COVID-19. Considering these facts, we evaluated the growth-inhibitory effects of three commonly used chemotherapy drugs, cisplatin, pemetrexed, and paclitaxel, in gefitinib-resistant non-small cell lung cancer (PC9GR) cells and investigated the underlying mechanism. Methods: In this study, flow cytometry (FCM) was used to profile the activity and function of human NK cells. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify cytokine levels. PC9GR cells were treated with cisplatin, paclitaxel, or pemetrexed as monotherapy for 72 h and then evaluated with a cell viability assay, a reactive oxygen species (ROS) assay, a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, SA-β-Gal staining, and Western blotting. Results: We demonstrated that NK cell dysfunction was linked to the reduced NK-mediated elimination of PC9GR cells. The PC9GR cells showed the marked secretion of IL-6, IL-8 and VEGF cytokines, which was connected to the activation of the inhibitory signaling pathway of NK cells. We found that paclitaxel was the most potent growth inhibitor, cisplatin had an intermediate growth inhibitory effect, and pemetrexed induced a minimal growth inhibitory effect in PC9GR cells. These growth inhibitory effects were observed to be associated with ROS-mediated DNA damage, which led to the activation of apoptotic caspases. Surprisingly, paclitaxel was the strongest remover of senescent cells; pemetrexed had an intermediate effect, and cisplatin removed the lowest number of senescent cells. Conclusions: In light of these findings, paclitaxel may have a better therapeutic effect than cisplatin or pemetrexed on PC9GR cells, suggesting that paclitaxel could offer a novel therapeutic approach for the treatment of gefitinib-resistant non-small cell lung cancer during the COVID-19 pandemic.