Albumin-bound paclitaxel augment temozolomide treatment sensitivity of glioblastoma cells by disrupting DNA damage repair and promoting ferroptosis

Abstract

Background Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic options available to restore TMZ treatment sensitivity. Here, we investigated the potential of albumin-bound paclitaxel (ABX), a novel microtubule targeting agent, in sensitizing GBM cells to TMZ and elucidated its underlying molecular mechanism. Methods A series of in vivo and in vitro experiments based on two GBM cell lines and two primary GBM cells were designed to evaluate the efficacy of ABX in sensitizing GBM cells to TMZ. Further proteomic analysis and validation experiments were performed to explore the underlying molecular mechanism. Finally, the efficacy and mechanism were validated in GBM patients derived organoids (PDOs) models. Results ABX exhibited a synergistic inhibitory effect on GBM cells when combined with TMZ in vitro. Combination treatment of TMZ and ABX was highly effective in suppressing GBM progression and significantly prolonged the survival oforthotopic xenograft nude mice, with negligible side effects. Further proteomic analysis and experimental validation demonstrated that the combined treatment of ABX and TMZ can induce sustained DNA damage by disrupting XPC and ERCC1 expression and nuclear localization. Additionally, the combination treatment can enhance ferroptosis through regulating HOXM1 and GPX4 expression. Preclinical drug-sensitivity testing based on GBM PDOs models confirmed that combination therapy was significantly more effective than conventional TMZ monotherapy. Conclusion Our findings suggest that ABX has the potential to enhance TMZ treatment sensitivity in GBM, which provides a promising therapeutic strategy for GBM patients.

Oridonin-induced ferroptosis and apoptosis: a dual approach to suppress the growth of osteosarcoma cells

“…Ferroptosis and apoptosis are two types of programmed cell death, involved in ferroptosis and apoptosis were extremely essential to the growth of different tumors, which also conferred resistance to anticancer drugs [ 52 – 54 ]. Targeting ferroptosis and apoptosis pathways were potential therapeutics for cancer, many medicines had been reported to play anti-cancer activities via the combination routes [ 55 ].…”

Oridonin-induced ferroptosis and apoptosis: a dual approach to suppress the growth of osteosarcoma cell

“…Given that the etiology of OS is complex, where multiple cell death mechanisms involved in OS's pathological process [49], it appears likely that the effective OS inhibitors should target multiple cell death processes simultaneously, which could also help address the problem of drug resistance [50]. The aberrant function of executioner and regulatory molecules involved in ferroptosis and apoptosis were extremely essential to the growth of different tumors [51], which also conferred resistance to anticancer drugs [52][53][54]. Targeting ferroptosis and apoptosis pathways were potential therapeutics for cancer strategy, many medicines had been reported to play anti-cancer activities via the combination routes.…”