ROS and RNS induced apoptosis through p53 and iNOS mediated pathway by a dibasic hydroxamic acid molecule in leukemia cells

• Published in: European journal of pharmaceutical sciences 2014-02, Vol.52, p.146-164
• Main Authors: Banerjee, Kaushik, Ganguly, Avishek, Chakraborty, Paramita, Sarkar, Avijit, Singh, Suryabhan, Chatterjee, Mitali, Bhattacharya, Subrato, Choudhuri, Soumitra Kumar
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzeneacetamides - pharmacology; Caspase 3 - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cells, Cultured; Glutathione - metabolism; HDAC3; Humans; Hydroxamic Acids - pharmacology; iNOS; Leukemia - drug therapy; Leukemia - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - physiology; Membrane Potential, Mitochondrial - drug effects; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Oxalates - pharmacology; p53; Reactive nitrogen species; Reactive Nitrogen Species - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2013.11.009

Anticancer drugs induce apoptosis to cancer cells and also exhibit undesired toxicity to normal cells. Therefore development of novel agents triggering apoptosis and have low toxicity towards normal cells is most important. Hydroxamic acids suppress tumour cell growth through apoptosis but the underlying mechanism is poorly understood. Herein, we describe the apoptotic potential of a dibasic hydroxamic acid derivative, viz., oxayl bis (N-phenyl) hydroxamic acid (OBPHA), which induces apoptosis through generation of both ROS and NO in doxorubicin resistant T-lymphoblastic leukemia, CEM/ADR5000 cells. Present study discloses that OBPHA selectively kills cancerous cells irrespective of their drug resistant phenotype. We also determined the crystal structure of OBPHA to understand the structural requirements for apoptosis; the study reveals that the presence of substituted hydroxamic acid groups (–CO–NH–OH) favours the generation of NO possibly through auto degeneration. Along with the induction of caspase 3 mediated intrinsic apoptosis; OBPHA also activates p53 dependent signalling cascade and downregulates HDAC3 expression in a time dependent manner possibly due to increased ROS and NO production and simultaneous decrease in cellular GSH level. Thus ROS and NO mediated downstream signalling are essential for the anticancer effect of OBPHA. Therefore OBPHA, having a structurally relevant pharmacophore provides important insight into the development of new ROS and RNS generating chemicals inducing p53 dependent apoptosis.