A Rationally Designed Bimetallic Platinum (II)-Ferrocene Antitumor Agent Induces Non-Apoptotic Cell Death and Exerts in Vivo Efficacy.

Despite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)-ferrocene hybrids that display multi-pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi-modal mechanism of action of these hybrid agents lead to non-apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.

Synthesis, biological evaluation, and molecular docking analysis of phenstatin based indole linked chalcones as anticancer agents and tubulin polymerization inhibitors.

A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.

Seaweed polysaccharide derived bioaldehyde nanocomposite: Potential application in anticancer therapeutics.

In the present study, we have demonstrated synthesis of agar aldehyde (Aald) from seaweed polysaccharide and its further successful application for preparation of Aald mediated solid silver nanocomposite (Aald-AgNPs). Aald-AgNPs were characterized for biophysical properties by FTIR, XRD, SEM, TEM, XPS, and UV-vis spectroscopy. Aald-AgNPs were further tested in vitro and in vivo for anticancer activity. The results of the in vitro study revealed that Aald-AgNPs exhibited activity against 3 cancer cell lines. Aald-AgNPs were found to act through causing dose dependent increase in cell size, inducing anueploidy, mitochondrial disintegration and increasing septa formation in cell cytoplasm. Results of in vivo anticancer activity against ME-180, Colon-26, and HL-60 xenograft mice tumor models showed 64 %, 27.3 % and 51 % reduction in tumor volume, respectively with 83-100 % survival rate. Aald-AgNPs exhibited excellent antibacterial activity. It was interesting to note that Aald-AgNPs did not exhibit any significant detrimental effect on viability and metabolic activity of normal bone marrow derived mesenchymal stem cells. This study opens new areas of research for chemists and biologists to use seaweed-derived polymers to develop nanocomposites for cancer therapeutics.

Differential cytotoxic activity of Quercetin on colonic cancer cells depends on ROS generation through COX-2 expression.

Quercetin is a bioactive compound with anti-inflammatory, antioxidant and anticancer properties. This study exemplifies the differential cytotoxic activity of Quercetin on two human colonic cancer cell lines, HT29 and HCT15. IC50 of Quercetin for HT29 and HCT15 cells were 42.5 µM and 77.4 µM, respectively. Activation of caspase-3, increased level of cytosolic cytochrome c, decreased levels of pAkt, pGSK-3ß and cyclin D1 in 40 µM Quercetin treated HT29 cells alone. Though, nuclear translocation of NFkB was increased in 40 µM Quercetin treated HT29 and HCT15 cells, over expression of COX-2 was observed in 40 µM Quercetin treated HT29 cells, whereas, Quercetin treated HCT15 cells did not expressed COX-2. Increased generation of reactive oxygen species (ROS) was observed only in Quercetin treated HT29 cells, which is due to over expression of COX-2, as COX-2 silencing inhibited Quercetin induced apoptosis and ROS generation. Insilico analysis provided evidence that Quercetin could partially inhibit COX-2 enzyme by binding to subunit A which has peroxidase activity and serves as source of ROS. However, Quercetin showed minimal effect on normal intestinal epithelial cells i,e IEC-6. To conclude, differential sensitivity of two cancer cells, HT29 and HCT15, to Quercetin depends on COX-2 dependent ROS generation that induces apoptosis and inhibits cell survival.