Abstract
TW-37 is a novel, potent and non-peptide Bcl-2 small-molecule inhibitor. Its activity in colorectal cancer (CRC) cells is studied. In both HCT-116 cells and primary human colon cancer cells, treatment with TW-37 at only nM concentration efficiently inhibited cell survival and proliferation. TW-37 also induced caspase-3/9 and apoptosis activation in CRC cells. Feedback autophagy activation was observed in TW-37-treated CRC cells. Reversely pharmacological autophagy inhibition or Beclin-1 knockdown by targeted-shRNA potentiated TW-37-induced apoptosis and killing of CRC cells. In vivo, intravenous injection of TW-37 inhibited HCT-116 tumor growth in mice. TW-37’s anti-tumor activity was further potentiated against Beclin-1-silenced HCT-116 tumors. Together, targeting Bcl-2 family protein by TW-37 efficiently inhibits CRC cell growth in vitro and in vivo. Inhibition of feedback autophagy activation could further sensitize TW-37.
Highlights
Colorectal cancer (CRC) is the third most-common human malignancy[1,2,3,4]
The current study examined its activity against human CRC cells
Treatment with TW-37 for 72 hours was more dramatic than 48 hours in suppressing HCT-116 cells (Fig 1A)
Summary
Colorectal cancer (CRC) is the third most-common human malignancy[1,2,3,4]. Each year, it is estimated that over one and half million new cases of CRC will be diagnosed [1,2,3,4]. There are two major categories of Bcl-2 family proteins, including the anti-apoptosis proteins (Bcl-2, Bcl-xL, Bcl-w, and Mcl-1), and the pro-apoptotic proteins (Bim, Puma, Bid, Bad, Bax, Bak and others)[7]. Recent studies have developed TW-37 as a novel, potent Bcl-2 small-molecule inhibitor [10,11,12,13] It inactivates multiple anti-apoptotic Bcl-2 family proteins[10,11,12,13]. TW-37 binds directly to BH3 domain-Bcl-2 family proteins to shut down the hetero-dimerization of pro-apoptotic proteins (Bid, Bim, and Bad) with Bcl-2. The current study examined its activity against human CRC cells
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