Retracted: TW‐37, a small‐molecule inhibitor of Bcl‐2, inhibits cell growth and invasion in pancreatic cancer

Abstract

Bcl-2 family of proteins plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting Bcl-2 family proteins would be extremely valuable for pancreatic cancer therapy. We have previously reported the synthesis and characterization of TW-37, which seems to be a negative regulator of Bcl-2. In this investigation, we tested our hypothesis whether TW-37 could be an effective inhibitor of cell growth, invasion and angiogenesis in pancreatic cancer cells. Using multiple cellular and molecular approaches such as MTT assay, apoptosis enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, Western blotting, electrophoretic mobility shift assay for measuring DNA binding activity of NF-κB, migration, invasion and angiogenesis assays, we found that TW-37, in nanomolar concentrations, inhibited cell growth in a dose- and time-dependent manner. This was accompanied by increased apoptosis and concomitant attenuation of NF-κB, and downregulation of NF-κB downstream genes such as MMP-9 and VEGF, resulting in the inhibition of pancreatic cancer cell migration, invasion and angiogenesis in vitro and caused antitumor activity in vivo. From these results, we conclude that TW-37 is a potent inhibitor of progression of pancreatic cancer cells, which could be due to attenuation of Bcl-2 cellular signaling processes. Our findings provide evidence showing that TW-37 could act as a small-molecule Bcl-2 inhibitor on well-characterized pancreatic cancer cells in culture as well as when grown as tumor in a xenograft model. We also suggest that TW-37 could be further developed as a potential therapeutic agent for the treatment of pancreatic cancer.

Evaluation and critical assessment of putative MCL-1 inhibitors

“…In order to specifically target multiple members of BCL-2 family, including MCL-1, several putative broad-spectrum BCL-2 family antagonists with improved specificity to inhibit MCL-1 have been developed. [16][17][18][19][20][21]24 One such broad-spectrum BCL-2 family antagonist, apogossypol, demonstrated modest selectivity in killing cells in a BAK-dependent manner, in agreement with our previous report (Figure 2). 9 Therefore, we assessed the specificity of different structural derivatives of apogossypol (BI97C1) and apogossypolone (BI97C10 and BI112D1), which were designed to possess enhanced binding affinities to MCL-1, in addition to other BCL-2 family members.…”

“…In marked contrast BI112D1 exhibited marked selectivity, only inducing apoptosis in cells reconstituted with BAK ( Figure 2). TW-37, a rationally designed benzenesulphonyl derivative that inhibits BCL-2, BCL-XL and MCL-1, 17 exhibited modest selectivity to the BAK-reconstituted Jurkat cells compared with BI97C1 and BI112D1. Neither BH3I-1 nor its structural derivatives, Figure 1 Chemical structures of different inhibitors used in this study.…”

“…Using a structure-based approach with gossypol as the starting material, TW-37, which bound more avidly to MCL-1 than BCL-2 or BCL-X L , was synthesised. 17 Of the inhibitors examined, TW-37 possibly offered the most promise in inducing apoptosis in a NOXA-dependent manner in MCL-1-dependent cells ( Figure 6). 3,32 As knockdown of NOXA led to incomplete inhibition of TW-37-induced apoptosis, other mechanisms, such as direct inhibition of MCL-1 and/or displacement of bound BH3-only proteins, including NOXA, may also be involved.…”

“…Several putative selective inhibitors of MCL-1, including obatoclax (GX-1570), 15 two derivatives of rhodanine (compounds 6 and 7), 16 TW-37, 17 derivatives of apogossypol/ apogossypolone (BI97C1 (commonly referred to as sabutoclax), BI97C10 and BI112D1 (also called BI97D6) [18][19][20] and MCL-1 inhibitor molecule (MIM-1) 21 have been synthesised based on different approaches including modelling studies, in silico and in vitro screens (Figure 1). In this study, we evaluate these compounds either as potentially selective MCL-1 inhibitors or as pan-BCL-2 family inhibitors.…”

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“…Gossypol,apogossypolone,TW-37,ABT-737,ABT-263 (navitoclax) andGX-015-070(Obatoclax) are small molecule inhibitors of Bcl-2 family proteins that have been shown to induce apoptosis of various cancer cells by blocking their anti apoptotic effects [60]. Gossypol, apogossypolon and TW-37 were specifically shown to effectively inhibit growth and invasion of pancreatic cancer cells [61][62][63].…”