Tris-Functionalized Polyoxotungstovanadate-Mediated Antitumor Efficacy Involves Multiple Cell Death Pathways

Polyoxometalates (POMs) are promising inorganic drug candidates for cancer chemotherapy. They are becoming attractive because of their easy accessibility and low cost. Herein, we report the synthesis and antitumor activity studies of four Lindqvist-type POMs with mixed-addenda atoms Na₂[V₄W₂O₁₆{(OCH₂)₃CR}] (R=-CH₂OH, -CH₃, -CH₂CH₃) and (Bu₄N)₂[V₃W₃{(OCH₂)₃CH₂OOCCH₂CH₃}]. Compared with the current clinical applied antitumor drug 5-fluorouracil (5-FU) or Gemcitabine, analysis of MTT/CCK-8 assay, colony formation and wound healing assay revealed that the {V₄W₂} POMs had acceptable cytotoxicity in normal cells (293T) and significant inhibitory effects on cell proliferation and migration in three human tumor cell lines: human lung carcinoma cells (A549), human cervical carcinoma cells (HeLa), and human breast cancer cells (MCF-7). Interestingly, among the POMs analyzed, the therapeutic index (TI) of the {V₄W₂} POM with R= -CH₂OH was relatively the most satisfactory. Thus, it was subsequently used for further studies. Flow cytometry analysis showed it prompted cellular apoptosis rate. qRT-PCR and Western blotting analysis indicated that multiple cell death pathways were activated including apoptosis, autophagy, necroptosis and pyroptosis during the POM-mediated antitumor process. In conclusion, our study shows that the polyoxotungstovanadate has great potential to be developed into a broad-spectrum antitumor chemotherapeutic drug.