title: ROS and RNS induced apoptosis through p53 and iNOS mediated pathway by a dibasic hydroxamic acid molecule in leukemia cells.
abstract: 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.
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Banerjee
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Avishek
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Avijit
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Chemistry, Banaras Hindu University, Varanasi, India.
authors.forename: Suryabhan
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Department of Chemistry, Banaras Hindu University, Varanasi, India.
authors.forename: Subrato
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India. Electronic address: soumitra01@yahoo.com.
authors.forename: Soumitra Kumar
authors.initials: SK
authors.lastname: Choudhuri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010070:Oxalates / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D010070:Oxalates; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C117053:oxalyl bis(N-phenyl)hydroxamic acid; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D005978:Glutathione
keywords: Apoptosis; HDAC3; Reactive nitrogen species; Reactive oxygen species; iNOS; p53