Abstract
Graphene oxide (GO) is a derivative of graphene and we recently uncovered that GO itself is sufficient to provoke both autophagy and toll-like receptor (TLR) responses in CT26 colon cancer cells and confer antitumor effects in immunocompetent mice bearing CT26 colon tumor. Cisplatin (CDDP) is an anticancer drug for the treatment of solid tumors by inducing cell death, but colon cancer cells have evolved chemoresistance to CDDP, hence compromising the therapeutic efficacy. Here we examined whether GO can act as a chemosensitizer to potentiate the efficacy of chemotherapy drugs. We found that combination of GO with irinotecan, doxorubicin and oxaliplatin failed to potentiate the killing of CT26 cells, but GO in combination with CDDP (GO/CDDP) significantly potentiated the CT26 cell killing mainly via necrosis and elicited CT26 autophagy. In addition to regular autophagic flux, GO/CDDP co-treatment also strikingly induced nuclear transport of autophagy marker LC3 and CDDP (but not GO), which was concomitant with the enhanced necrosis. Prior treatment of cells with nuclear import inhibitor (ivermectin) or cell necrosis inhibitor (necrostatin-1) hindered the import of LC3 puncta and CDDP into the nucleus and impaired the cell necrosis. Intratumoral injection of GO/CDDP into colon cancer in mice augmented the antitumor effects, enhanced the intratumoral autophagy, necrosis and immune cell infiltration. These data collectively demonstrated that combination of GO and CDDP synergistically triggers autophagy, necrosis and suppresses tumor growth, thus implicating the potentials of GO as a chemosensitizer of CDDP in colon cancer chemotherapy.