title: Sensitization of cancer cells to cyclophosphamide therapy by an organoselenium compound through ROS-mediated apoptosis.
abstract: Induction of apoptosis has been recognized as an excellent therapeutic approach in cancer. Selenium based compounds are well known for their antitumor and synergistic chemotherapeutic efficacy when combined with a standard antineoplastic drug. Previously, we have reported that an organoselenium compound, diphenylmethyl selenocyanate (DMSE) could effectively protect normal organs and tissues from the toxicity induced by a standard chemotherapeutic drug cyclophosphamide in a tumor bearing mouse model. In this study, as a further step, we have evaluated the effect of DMSE in sensitization of tumor cells to cyclophosphamide-induced cell death. We found that DMSE alone or in combination with cyclophosphamide could induce cell death mainly through apoptosis. Generation of reactive oxygen species (ROS) followed by down-regulation of antioxidant defense system in the tumor cells was hypothesized as the crucial cellular events occurred following DMSE treatment. In addition, DMSE in combination with cyclophosphamide also caused DNA damage in tumor cells which might be due to the consequence of oxidative stress induced by the combined therapy. Moreover, production of ROS subsequently activated p53, which in turn initiated release of mitochondrial cytochrome c via up-regulation of Bax and down-regulation of Bcl-2. Ultimately, the activation of caspase-3 played the major role to cleave PARP that finally led to apoptosis. All the above results together proposed that, DMSE sensitized tumor cells to cyclophosphamide therapy through ROS-induced p53 activation and mitochondria-mediated caspase dependent apoptosis.
authors.affiliation: Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, Kolkata 700026, India.
authors.forename: Pramita
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, Kolkata 700026, India; Centre of Biomedical Research, SGPGIMS Campus, Lucknow 226014, India.
authors.forename: Somnath Singha
authors.initials: SS
authors.lastname: Roy
authors.affiliation: Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, Kolkata 700026, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Basu
authors.affiliation: Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, Kolkata 700026, India. Electronic address: sudinb19572004@yahoo.co.in.
authors.forename: Sudin
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D016566:Organoselenium Compounds / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000502:physiology
chemical_list: D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C495419:diphenylmethyl selenocyanate; D003520:Cyclophosphamide
keywords: Antioxidant defense system; Chemosensitization; DNA damage; Diphenylmethyl selenocyanate; Mitochondrial pathway of apoptosis; Oxidative stress