Date of Award

2026

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Zhe-Sheng Chen

Second Advisor

Sandra Reznik

Third Advisor

John N. D. Wurpel

Abstract

Cancer is still one of the major public health challenges worldwide to the present day. Multi-drug resistance (MDR) that occurs in cancer chemotherapies is a non-negligible cause of cancer treatment failure and tumor recurrence. Overexpression of ATP-binding cassette (ABC) transporters is one of the most frequent mechanisms of MDR occurrence. Therefore, the establishment of a chemotherapy agent whose anticancer efficacy would not be affected by the overexpression of ABC transporters is in demand. Methyl-cantharidimide (MCA), a cantharidin (CTD) analog, has been approved in China for clinical liver cancer treatment. This study revealed that MCA was efficacious in the ABCB1-, ABCG2-mediated MDR cancer cells and cisplatin-resistant cancer cells. What’s more, the MCA treatment can inhibit cell colony formation in the liver cancer cells. To explore the underlying mechanisms of MCA’s anticancer efficacy, further investigations demonstrated that MCA treatment in liver cancer cells could induce cell apoptosis and cell cycle arrest in the G2/M phase. Bioinformatic analysis indicated that down regulation of cyclin-dependent kinase 1 (CDK1) might be involved in the MCA-induced cell cycle arrest. Expression inhibition of CDK1 was observed in MCA treated liver cancer cells by both immunoblot and immunofluorescence assay. Induction of reactive oxygen species (ROS) production was observed after MCA treatment in liver cancer cells. Furthermore, our investigation indicated that MCA-induced apoptosis was involved with ROS dependent oxeiptosis pathway, instead of typical Bax/Bcl-2 and caspase pathways. The toxicity of MCA to liver cancer cells was retained in the 3D multicellular tumor spheroids model (MCTSs), which mimicked in vitro condition. In the tumor xenograft mouse model, tumor shrinking was observed after MCA treatment. Overall, our study claimed that MCA is not confirmed to be resistant to ABCB1, ABCG2-overexpressing, or cisplatin-resistant cancer cells. And MCA’s anticancer efficacy is due to its function in inducing oxeiptosis and cell cycle arrest in the G2/M phase.

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