Background: Lung cancer remains a leading cause of cancer-related mortality worldwide, and effective management is hindered by limited therapeutic options. Marsdenia tenacissima (MT), a traditional Chinese medicinal herb, enhances the anti-tumor efficacy of paclitaxel (PTX). However, the specific bioactive constituents and the underlying mechanisms responsible for this chemosensitization remain largely undefined.
Methods: Bioassay-guided isolation of MT extract led to the identification of 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2). In vitro cytotoxicity was assessed using Lewis lung carcinoma (LLC) cells via cell viability, apoptosis, and cell-cycle flow cytometry analyses. Molecular mechanisms were interrogated via Western blotting. In vivo efficacy and safety were evaluated using C57BL/6 LLC and HepG2 murine xenograft models treated with MT2 and PTX combinations, followed by histological liver evaluation.
Results: MT2 alone exhibited minimal cytotoxicity but significantly potentiated PTX-mediated cytotoxicity in LLC cells. The combination treatment induced superior cell-cycle arrest and late-stage apoptosis compared to PTX monotherapy, driven by the suppression of pro-survival pathways upregulation of apoptotic signaling. In vivo, five intraperitoneal doses of MT2+PTX (30 and 10 mg/kg, respectively) produced synergistic tumorigenic inhibition without observable hepatic toxicity. Furthermore, this chemosensitizing effect extended to the HepG2 xenograft model.
Conclusions: MT2 is a potent, non-toxic chemosensitizer that significantly enhances the anti-tumor efficacy of paclitaxel across multiple preclinical cancer models. These findings support the clinical development of MT2-paclitaxel combination therapy to improve therapeutic outcomes in lung and other refractory cancers.