Combining AdipoRon with Paclitaxel Unveils Synergistic Potential in Non-Small Cell Lung Cancer Cells via AMPK-ERK1/2 Signaling

As part of chemotherapy regimens, Paclitaxel improves the overall survival of many non-small cell lung cancer (NSCLC) patients. However, the development of drug resistance and adverse events limits its clinical usage, reinforcing the need for further advancements in NSCLC therapeutics. We recently recognized the adiponectin receptor agonist AdipoRon as a promising anticancer compound in NSCLC. Consequently, this study aimed to evaluate the therapeutic potential of combining AdipoRon with Paclitaxel (Combo) in NSCLC cells. With respect to individual treatments, Combo triggered a stronger inhibition of both cell growth and clonogenic potential, as well as a greater induction of cell death. The Combo-mediated cytotoxicity was also corroborated by cleavage of poly-ADP ribose polymerase (PARP) and caspase-3 apoptotic markers. Notably, AMP-activated protein kinase (AMPK) emerged as a critical sensor in Combo efficacy, as its inhibition by Compound-C unveiled a significant rescue in cell growth. Although Combo caused a gradual downregulation of extracellular signal-regulated kinase 1/2 (ERK1/2), the hindrance in the upstream cascade by PD98059 partially counteracted the Combo outcomes. In conclusion, our findings designate AdipoRon as an effective candidate in Paclitaxel-based therapy. Nevertheless, future studies aimed at exploring the Combo aptitude in overcoming the Paclitaxel-related restraints need to be investigated in NSCLC.