Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

We demonstrated that VB1 promoted apoptosis via p53‐dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax activation and mitochondrial dysfunction in colon cancer HCT‐116 and LoVo cells. And we provide a novel insight for the antitcancer mechanism of VB1 and scientific rationale for further development of VB1 as a novel anticancer drug used alone or in combination with other chemotherapeutic agents in the treatment of colorectal cancer clinically.

Abstract

Purified vitexin compound 1 (VB1, a neolignan isolated and extracted from the seed of Chinese herb Vitex negundo) is an effective antitumor agent and exhibits promising clinical activity against various cancers including colorectal cancer. However, it remains unknown about the precise underlying mechanism associated with the antitumor effect of VB1 and how it triggers apoptosis in cancer cells. Here, we demonstrated that VB1 promoted apoptosis via p53‐dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax (Bcl‐2‐associated X protein) activation and mitochondrial dysfunction in colon cancer HCT‐116 and LoVo cells. Deficiency in p53, PUMA, or Bax abrogated VB1‐induced apoptosis and promoted cell survival in HCT‐116 cells. Furthermore, the combination of VB1 with chemotherapeutic drugs 5‐fluorouracil (5‐FU) or NVP‐BZE235 resulted in a synergistic antitumor effect via PUMA induction in HCT‐116 cells. VB1 significantly suppressed the cell proliferation of wild‐type (WT) HCT‐116 and LoVo cells in vitro and tumor growth in vivo. The results indicate that p53/PUMA/Bax axis plays a critical role in VB1‐induced apoptosis and VB1 may have valuable clinical applications in cancer therapy as a novel anticancer agent used alone or in combination with other chemotherapeutic drugs.

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