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Carbon ion (C12) radiotherapy is becoming very promising to kill highly metastatic cancer cells keeping adjacent normal cells least affected. Our previous study shows that combined PARP-1 inhibition with C12ion reduces MMP-2,-9 synergistically but detailed mechanism is not clear. To understand this mechanism and the rationale of using PARP-1 inhibitor with C12radiotherapy for better outcome in controlling metastasis, we investigated in- vitro metastasis in A549 cells exposed with C12in presence and absence of PARP-1 inhibition using siRNA or olaparib. Our experiments show that C12and PARP-1 inhibition separately reduces cell proliferation, cell migration, wound healing and reduces MMP-2, -9 expressions. Notably, N-cadherin, vimentin, anillin are decreased and claudin-1, -2 are increased by each single treatment whereas combined treatment synergistically alters these proteins to suppress epithelial-mesenchymal transition (EMT) process. So, the transcription of MMP- 2,-9 and key proteins in EMT pathways are targeted by both C12and olaparib. Hence, C12radiotherapy could potentially be combined with olaparib as chemotherapeutic agent for better control of cancer metastasis. [ABSTRACT FROM AUTHOR]

Carbon ion (C12) radiotherapy is gradually becoming promising modality of treatment over conventional x-ray or gamma rays against various deep-seated inoperable cancers although details cellular response against C12 ion exposure is largely unknown. C12 ion exposure predominantly produces double strand breaks or 'cluster DNA damage' which is difficult to repair. Poly (ADP-ribose) polymerase-1 (PARP-1) is well-known repair enzyme and a number of PARP-1 inhibitors are in clinical trial for its radio sensitization. But role of PARP-1 in cluster DNA damage is poorly understood. Our aim was to investigate role of PARP-1 in DNA repair after damage by high LET C12 ion. A549 cells were exposed with C12 ion in presence and absence of PARP-1 inhibitor rucaparib. Then DNA breaks were measured by gamma H2AX foci. Expression of candidate genes like Ku70, Ku80, MRE11, Rad50, Rad51 and Rad52 involved in double strand repair were studied in A549 cells treated with C12 with and without rucaparib. We observed that 1 µM rucaparib treatment or 1Gy C12 reduced expression of all the genes significantly. However, combined treatment just abolished the expression. This data implicates that rucaparib sensitizes A549 cells to C12 ion by down-regulating several candidate genes involved in HR and NHEJ pathways of DNA repair pathway. So, rucaparib interferes HR and NHEJ pathway by down-regulating candidate genes and thereby sensitizes A549 cells to C12 ion exposure. [ABSTRACT FROM AUTHOR]