Novel ruthenium(II) triazine complex [Ru(bdpta)(tpy)]2+ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…Some small molecule inhibitors of GRP78 were also tested in CSC-related models [80,238,239]. In particular, the known GRP78 inhibitor HA15 (N- -1naphthalenyl]sulfonyl]amino]phenyl]-2-thiazolyl]-acetamide), if combined with PRDM14 knockdown, diminished the fraction of CSC-like SP cells in breast cancer HCC1937 cells [80].…”

“…Zebularine, a cytidine analog and inhibitor of DNA methylation, was shown to suppress stemness manifestations in colonosphere-forming colorectal cancer HCT116 cells by downregulating GRP78, while upregulating CHOP, a pro-apoptotic factor [238]. Another inhibitor of GRP78, ruthenium(II) triazine complex [Ru(bdpta)(tpy)] 2+ , reduced the GRP78 protein level in CD133+ CSCs derived from human colon cancer HCT-116 cells; the inhibitor-induced GRP78 downregulation was correlated in a dose-dependent manner with the in vivo-achieved antitumor effects toward tumor xenografts [239]. The cited findings [80,238,239] confirm the rationale of further development of small molecule inhibitors of GRP78 to target cancer stemness.…”

Applications of Ruthenium Complex in Tumor Diagnosis and Therapy

“…This prospect is extremely enlightening, and antitumor drugs with better efficacy than that of existing chemotherapeutic drugs, which are ineffective in treating certain tumors, could be developed. Furthermore, the prospective agents could be effective against tumors that have developed drug resistance for their potent efficacy ( Wang N. et al, 2015 ; Purushothaman et al, 2018 ). The results of clinical studies should be reflectively considered in determining the reasons for the failure of the clinical investigations of NAMI-A and KP1019, which could lead to design drugs with less side effects, greater selectivity, and higher bioavailability.…”

Multifunctional TPP-PEG-biotin self-assembled nanoparticle drug delivery-based combination therapeutic approach for co-targeting of GRP78 and lysosome

“…In addition, ruthenium(III, II) complexes have shown strong affinities towards thiol containing proteins such as bovine serum albumin (BSA), glutathione (GSH), and transferrin [9]. Particularly, their strong affinities to transferrin is known to cause more accumulation in cancer cells than in normal cells due to an active metabolism that needs more Fe 2+ ion [10,11]. TPP-PEG-biotin is a PDT substance that produces reactive oxygen species (ROSs) by irradiation at 660 nm [12].…”

“…The co-targeting of GRP78 and lysosome is expected to be a very efficient anti-cancer therapeutic strategy in that the worst energy efficiency is given to cancer cells. In the previous work [11], Ru-1 has been identified as a potent anticancer agent against drug resistant cancer stem cells (CSCs). The hydrophobic property inherent to Ru-1 requires assistance of NDDS for active use of Ru-1 in a wide range of biomedical applications.…”