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Specific focus on "redox cancer therapy" by targeting drugs to redox homeostasis of the cancer cells is growing rapidly. Recent clinical studies showed that N-acetyl cysteine (NAC) treatment significantly decreased the metabolic heterogeneity and reduced Ki67 (a proliferation marker) with simultaneous enhancement in apoptosis of tumor cells in patients. However, it is not yet precisely known how thiol antioxidants enhance killing of cancer cells in a context dependent manner. To this end, we showed that a dietary compound, malabaricone C (mal C) generated copious amounts of reactive oxygen species (ROS) and also reduced GSH level in lung cancer cells. Paradoxically, although antioxidants supplementation reduced mal C-induced ROS, thiol-antioxidants (NAC/GSH) restored intracellular GSH level but enhanced DNA DSBs and apoptotic cell death induced by mal C. Our results unraveled two tightly coupled biochemical mechanisms attributing this sensitization process by thiol antioxidants. Firstly, thiol antioxidants enable the "catechol-quinone redox cycle" of mal C and ameliorate ROS generation and bio-molecular damage (DNA and protein). Secondly, thiol antioxidants cause rapid glutathionylation of transcription factors [p53, p65 (NF-κB) etc.], oxidized by mal C, and abrogates their nuclear sequestration and transcription of the anti-apoptotic genes. Furthermore, analyses of the mitochondrial fractions of p53 expressing and silenced cells revealed that cytoplasmic accumulation of glutathionylated p53 (p53-SSG) triggers a robust mitochondrial death process. Interestingly, mutation of redox sensitive cysteine residues at 124, 141 and 182 position in p53 significantly reduces mal C plus NAC mediated sensitization of cancer cells. The preclinical results, in two different tumor models in mice, provides further support our conclusion that NAC is able to sensitize mal C induced suppression of tumor growth in vivo. Image 1 • Thiol antioxidants enhance sensitivity of lung cancer cells to mal C. • Mal C induces generation of site-specific ROS and S-glutathionylation of redox sensitive proteins. • P53 glutathionylation causes its higher accumulation in mitochondria, laeding to apoptosis. • Mal C and thiol antioxidants effectively reduces lung tumor growth in mice. [ABSTRACT FROM AUTHOR]

Cisplatin (cis-diamminedichloro-platinum, CDDP), is a widely used platinum compound for various solid tumors including breast cancer as first line of therapy. However, its positive effects are limited due to acquired drug resistance and severe side effects in non-malignant tissue, especially due to dose-dependent nephro- and/or neuro-toxicity. Salinomycin is an antibiotic with coccidiostat effect and has shown anticancer efficacy against various cancer cells with selectivity in targeting cancer stem cells. In the present study, anticancer efficacy and mechanism of action of salinomycin in CDDP-resistant human breast cancer (MCF7DDP) cells has been examined. Initially, we generated CDDP-resistant cells by a new protocol followed by checking the anticancer efficacy of salinomycin through MTT, clonogenic, annexin-V/PI and sub-G1 assay. Our results demonstrated that salinomycin diminished both cell proliferation and metastatic migration of MCF7DDP cells. Salinomycin also induced mitochondrial dysfunction in CDDP-resistant breast cancer cells. The analysis of nuclear translocation of pro-survival transcription factors by western blotting showed a distinct role of p65 (NF-κB) in CDDP-mediated resistance in breast cancer. Salinomycin abrogated nuclear translocation of NF-κB proteins and also caused a concurrent reduction in NF-κB regulated expression of pro-survival proteins e.g. , survivin, XIAP and BCL-2 in CDDP-resistant cells. These results suggest that a follow up treatment of salinomycin may be promising strategy against CDDP resistant breast cancer cells and metastasis and help in reducing CDDP-induced side effects. • Salinomycin inhibits cell viability of both ER positive breast cancer and CDDP resistant breast cancer (MCF7DDP) cells. • Salinomyin treatment induces apoptosis and reduces metastatic potential of MCF7DDP cells. • Salinomycin targets mitochondria though deregulation of mitochondrial membrane proteins in CDDP resistant breast cancer. • Salinomycin targets NF-κB to abrogate CDDP mediated resistance in cancer cells. [ABSTRACT FROM AUTHOR]

The syntheses of three water-soluble glucose-conjugated BODIPY dyes with different wavelength emissions and studies of their photodynamic therapeutic (PDT) action on human lung cancer A549 cell line are disclosed. Amongst the chosen compounds, the BODIPY dye 4 possessing a glycosylated styryl moiety at the C-3 position showed best PDT property against the A549 cell line. In particular, it induced reactive oxygen species-mediated caspase-8/caspase-3-dependent apoptosis as revealed from the increased sub G1 cell population and changes in cell morphology. These results along with its localization in the endoplasmic reticulum, as revealed by confocal microscopy suggested that mitochondria may not be directly involved in the photo-cytotoxicity of 4 . Compound 4 did not induce any dark toxicity to the A549 cells, and was non-toxic to normal lung cells. [ABSTRACT FROM AUTHOR]