OZ-001 Suppresses the Growth of Triple-Negative Breast Cancer and Pancreatic Cancer by Targeting STAT3 Phosphorylation and the Calcium Signaling Pathway.

Abstract

Triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are aggressive malignancies characterized by uncontrolled tumor growth, high recurrence rates, and resistance to chemotherapy. OZ-001 is a small molecule with a dual mechanism of action targeting T-type Ca2+ channels and inhibiting activation of the signal transducer and activator of transcription 3 (STAT3) protein. These properties suggest a potential use as a therapeutic agent for TNBC and PDAC, addressing the urgent need for effective treatments. This study evaluates the anticancer efficacy and underlying mechanism of action of OZ-001. The anticancer activities of OZ-001 were assessed in MDA-MB-231 cells (against TNBC) and MIA PaCa-2 cells (against PDAC) through analyses of cell viability, apoptosis, protein characterization, and cell cycles. Protein affinity and intracellular calcium measurements were conducted to investigate its effects on STAT3 and T-type calcium channels. Xenograft animal models were developed using MDA-MB-231 and MIA PaCa-2 cells to evaluate the in vivo anticancer effects of OZ-001. We found that OZ-001 induced caspase-dependent MDA-MB-231 and MIA PaCa-2 cells by modulating Bcl-2 family proteins. It suppressed STAT3 phosphorylation, reducing the expression of survivin, Bcl-2, and cyclin D1. Specifically, OZ-001 blocked T-type calcium channels, which reduced intracellular calcium levels and activated apoptotic pathways. In vivo, oral administration of OZ-001 significantly reduced tumor growth in both xenograft models, likely due to diminished STAT3 phosphorylation and associated tumorigenic processes. These findings demonstrate the potential of OZ-001 to serve as an effective therapeutic agent for treating TNBC and PDAC.