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. Author manuscript; available in PMC: 2014 Oct 16.
Published in final edited form as: Cancer Metastasis Rev. 2014 Mar;33(1):285–294. doi: 10.1007/s10555-013-9450-8

Fig. 3.

Fig. 3

A novel combination therapy model. a ABT-263 (Navitoclax) is developed for use in the clinic and an oral version of ABT-737. It binds to and inhibits Bcl-2, Bcl-XL, and Bcl-w with higher affinities than any of other Bcl-2 inhibitors, resulting in effective enhancement of the cytotoxicity of several chemotherapy agents. b However, resistance against ABT-263 is observed in cancer cells that express Mcl-1 because ABT-263 does not bind to Mcl-1. On the other hand, Gal-3 that highly expresses in diverse cancers have multiple roles in the regulation of apoptosis (as shown in Fig. 2). Gal-3 may replace or mimic Bcl-2 by binding to Bax through the NWGR motif, which is critical for the antiapoptotic function of both Bcl-2 and Gal-3 proteins. c We propose a novel combination therapy model. Combination therapy targeting Gal-3 using sugar-binding antagonist with the conventional anti-Bcl-2 treatment leads to suppression of antiapoptotic function of Gal-3 itself. Interestingly, GCS-100, which binds to Gal-3 as an antagonist, is shown to reduce Mcl-1 expression and regulate the other bcl-2 family proteins. In addition, targeting the CRD of Gal-3 containing the NWGR motif may induce release of Bax from Gal-3, subsequently resulting in MOMP