Graphene oxide sensitizes cancer cells to chemotherapeutics by inducing early autophagy events, promoting nuclear trafficking and necrosis

Abstract

Rationale: Cisplatin (CDDP) is a broad-spectrum anticancer drug but chemoresistance to CDDP impedes its wide use for cancer therapy. Autophagy is an event occurring in the cytoplasm and cytoplasmic LC3 puncta formation is a hallmark of autophagy. Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we aimed to evaluate whether combined use of GO with CDDP (GO/CDDP) overcomes chemoresistance in different cancer cells and uncover the underlying mechanism.Methods: We treated different cancer cells with GO/CDDP and evaluated the cytotoxicity, death mechanism, autophagy induction and nuclear entry of CDDP. We further knocked down genes essential for autophagic flux and deciphered which step is critical to nuclear import and cell death. Finally, we performed immunoprecipitation, mass spectrometry and immunofluorescence labeling to evaluate the association of LC3 and CDDP.Results: We uncovered that combination of GO and CDDP (GO/CDDP) promoted the killing of not only CT26 cells, but also ovarian, cervical and prostate cancer cells. In the highly chemosensitized Skov-3 cells, GO/CDDP significantly enhanced concurrent nuclear import of CDDP and autophagy marker LC3 and elevated cell necrosis, which required autophagy initiation and progression but did not necessitate late autophagy events (e.g., autophagosome completion and autolysosome formation). The GO/CDDP-elicited nuclear trafficking and cell death also required importin α/β, and LC3 also co-migrated with CDDP and histone H1/H4 into the nucleus. In particular, GO/CDDP triggered histone H4 acetylation in the nucleus, which could decondense the chromosome and enable CDDP to more effectively access chromosomal DNA to trigger cell death.Conclusion: These findings shed light on the mechanisms of GO/CDDP-induced chemosensitization and implicate the potential applications of GO/CDDP to treat multiple cancers.

Cellular Signaling Pathways Activated by Functional Graphene Nanomaterials

“…The anticancer drug delivery system induces the initiation of autophagy, which precedes cellular death. In particular, the nuclear translocation of either the LC3 autophagic marker and the chemotherapy drug is stimulated and results in the shut off of the late autophagy events and activation of cell death signals [ 43 ].…”

Hybrid nanocomposite curcumin-capped gold nanoparticle-reduced graphene oxide: Anti-oxidant potency and selective cancer cytotoxicity

“…To this end, graphene constitutes a promising platform for insoluble drug delivery [115]. Additionally, in a recent work by Lin et al (2018), graphene oxide itself induced higher cytotoxicity towards colon cancer cells, among different panels of cancer types tested [116]. This remarkably points to a potential synergistic effect exerted by graphene and the loaded drug against colon cancer.…”

Magnetic Graphene Oxide Nanocarrier for Targeted Delivery of Cisplatin: A Perspective for Glioblastoma Treatment

“…In the absence of NGO, a fast CisPt release was recorded (M t /M 0 of 0.90 after 20 h), with high α value indicating a low affinity of the drug towards the carrier phase (γ-Fe 2 O 3 ). On other hand, the strong interaction between CisPt and NGO [60,61,62] resulted in a more extended release over time (F max < 0.8 even after 250 h), with the same affinity (3.54) recorded for either NGO or γ-Fe 2 O 3 @NGO. The presence of γ-Fe 2 O 3 in γ-Fe 2 O 3 @NGO was found to slow the release, with reduced kinetic constant (k R ) and t 1/2 values moving from 19.01 (NGO) to 29.38 (γ-Fe 2 O 3 @NGO) h. This could be ascribed to the hindrance to the drug diffusion from the NGO to the solvent phase by the oleate coating of γ-Fe 2 O 3 nanoparticles [55].…”