Benzothiazinone [BSA]

The serine synthesis pathway (SSP) is active in multiple cancers. Previous study has shown that bortezomib (BTZ) resistance is associated with an increase in the SSP in multiple myeloma (MM) cells; however, the underlying mechanisms of SSP-induced BTZ resistance remain unclear. In this study, we found that phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in the SSP, was significantly elevated in CD138(+) cells derived from patients with relapsed MM. Moreover, high PHGDH conferred inferior survival in MM. We also found that overexpression of PHDGH in MM cells led to increased cell growth, tumour formation, and resistance to BTZ in vitro and in vivo, while inhibition of PHGDH by short hairpin RNA or NCT-503, a specific inhibitor of PHGDH, inhibited cell growth and BTZ resistance in MM cells. Subsequent mechanistic studies demonstrated PHGDH decreased reactive oxygen species (ROS) through increasing reduced glutathione (GSH) synthesis, thereby promoting cell growth and BTZ resistance in MM cells. Furthermore, adding GSH to PHGDH silenced MM cells reversed S phase arrest and BTZ-induced cell death. These findings support a mechanism in which PHGDH promotes proliferation and BTZ resistance through increasing GSH synthesis in MM cells. Therefore, targeting PHGDH is a promising strategy for MM therapy.

The solvothermal reaction of Cd(NO3)(2)center dot 4H(2)O with different donor ligands afforded two new Cd(II)-based coordination polymers [Cd(Hcia)(btz)](n) (1, H(3)cia = 5-(4-carboxyphenoxy)isophthalic acid, btz = 4,4'-bi(1,2,4-triazole)) and {[Cd(2,2-bpy)(NO3)(2)(H2O)](DMA)}(n) (2, 2,2'-bpy = 2,2'-bipyridine). Complex 1 shows a 3 D 2-fold interpenetrated network based on 1 D infinite [-btz-Cd-btz-] chains, and complex 2 shows 1 D chain-like network based on the 2,2'-bpy chelating Cd centers extended by the NO3- ions. Furthermore, the CCK-8 assay and Annexin V-FITC/PI detection was performed to evaluate the anti-cancer activity of the two complexes against the Hey ovarian cancer cell lines. Western blot was conducted for the mechanism evaluation of the complexes.