High let carbon ion (¹²C) combined with parp inhibitor olaparib could be a promising approach of cancer therapy against highly aggressive human nonsmall lung cancer cells

Carbon ion radiotherapy (CIRT) becoming very popular over conventional gamma or X-rays because of its several advantages over conventional photon therapy and is a very good alternative to surgery - sometimes inevitable for inoperable tumors like lung and other tumors. Poly (ADP-ribose) polymerase inhibitor (PARPi) long been known as chemo/radiosensitizer. PARPi olaparib alone shows good effect against various cancer types. Combined radiotherapy with a suitable drug is always better than a single mode. Our objective was to insight into mechanism(s) of interference of DNA repair pathways followed by apoptosis and inhibition of metastasis by ¹²C ion exposure in combination with PARPi olaparib in NSCLC. We have monitored cell viability, DNA damage, intrinsic and extrinsic pathways of apoptosis, HR and NHEJ pathway, cell migration, wound healing, and various signaling pathways of MMPs activation and epithelial-mesenchymal transition (EMT) pathways in p53 wild type A549 and p53 null H1299 cells after exposure with high LET ¹²C ion with and without olaparib. We observed that ¹²C ion treatment was more lethal than the corresponding dose of gamma. ¹²C-ion markedly inhibits both HR and NHEJ pathways, culminating in DNA damage-induced apoptosis via activation of caspase-8, -9, -3, nucleosomal ladder formation. ¹²C ion reduced cell proliferation, cell migration, wound healing, and phosphorylation of EGFR, Akt, p38, ERK resulting in inactivation of NF-kB. It also altered some of the key players in the epithelial-mesenchymal transition (EMT) pathway like N-cadherin, vimentin, anillin, claudin-1 to reduce metastasis potential in A549. However, 99olaparib combined with ¹²C-ion significantly inhibits repair pathways and cell metastasis compared with ¹²C-ion treatment alone, especially in p53 null H1299 cells. CIRT, especially when combined with olaparib, shows promise as a treatment for highly metastatic and inoperable NSCLC, offering a powerful alternative for tumors with challenging profiles like p53 mutations. (author)