Preclinical study of cinobufagin as a promising anti-colorectal cancer agent.

Xing-Sheng Lu,Min-Bin Chen,Chun-Gen Xing,Yin-Biao Qiao,Bo Yang,Ya Li

doi:10.18632/oncotarget.13519

Abstract

Here, we assessed the anti-colorectal cancer (CRC) cell activity of cinobufagin (CBG). We found that CBG exerted potent cytotoxic and anti-proliferative activity against CRC lines (HCT-116 and HT-29) and primary human CRC cells. Meanwhile, it activated apoptosis, and disrupted cell-cycle progression in the cells. At the signaling level, CBG treatment in CRC cells provoked endoplasmic reticulum stress (ER stress), the latter was evidenced by caspase-12 activation, CHOP expression, as well as PERK and IRE1 phosphorylations. Contrarily, the ER stress inhibitor salubrinal, the caspase-12 inhibitor and CHOP shRNA remarkably attenuated CBG-induced CRC cell death and apoptosis. Further, CBG in-activated mammalian target or rapamycin complex 1 (mTORC1), which appeared responsible for proliferation inhibition in CRC cells. Introduction of a constitutively-active S6K1 (“ca-S6K1”) restored proliferation of CBG-treated CRC cells. Finally, CBG intraperitoneal injection suppressed HCT-116 xenograft tumor growth in the nude mice. CHOP upregulation and mTORC1 in-activation were also noticed in CBG-treated HCT-116 tumors. The results of this preclinical study suggest that CBG could be tested as promising anti-CRC agent.

Highlights

Colorectal cancer (CRC) is a major threat to human health, and it ranks one of leading causes of cancerrelated mortalities in the world [1,2,3]
We found that CBG exerted potent cytotoxic and anti-proliferative activity against colorectal cancer (CRC) lines (HCT-116 and HT-29) and primary human CRC cells
We provided evidences to show that CBG-induced CRC cell death is associated with Endoplasmic reticulum (ER) stress activation

Summary

Introduction

Colorectal cancer (CRC) is a major threat to human health, and it ranks one of leading causes of cancerrelated mortalities in the world [1,2,3]. Treatment cancer cells with Traditional Chinese Medicine (TCM) has been a research focus for many years [12]. One of these TCM, Chansu, is extracted from parotoid glands of the Chinese toad [13]. Cinobufagin (CBG) is a primary and active component from Chansu [14]. Recent preclinical studies have tested its anti-cancer activity [15,16,17]. Its potential effect in CRC cells has not been extensively studied. The underlying signaling mechanisms of CBG-mediated cancer cell killing effect are largely unknown

Methods

Results

Conclusion