Pramita Chakraborty

Modulation of Cyclophosphamide-Induced Cellular Toxicity by Diphenylmethyl Selenocyanate In Vivo, an Enzymatic Study

AIM: Cyclophosphamide (CP) is one of the most widely used alkylating antineoplastic agents that damage normal cells while killing cancerous cells in vivo. The use of CP in treating cancer patients is limited due to its severe toxicities induced mainly by oxidative stress. Diphenylmethyl selenocyanate is a synthetic organoselenium compound shown to act as a potent antioxidant in chemically induced murine toxicity and carcinogenesis models in vivo. In the present study, this compound has been evaluated for its protective potential against CP-induced toxicity in Swiss albino mice. METHODS: CP was administered intraperitoneally (50 mg/kg) and diphenylmethyl selenocyanate was given orally (3 mg/kg) in a pretreatment and concomitant treatment schedule, and the effects were assessed by estimating lipid peroxidation level, phase II detoxifying enzyme system, blood hemoglobin level, serum transaminase activity, and nitrite content. RESULTS: Diphenylmethyl selenocyanate significantly (P＜0.05) increased glutathione-S-transferase, glutathione peroxidase, and catalase levels whereas decreased the lipid peroxidation levels in both liver and lung tissues of the animals given CP. Superoxide dismutase was increased significantly in liver (P＜0.05) but not in the lung. The selenium compound also significantly (P＜0.05) increased the blood hemoglobin level whereas decreased the transaminase activity in serum and the nitrite content in peritoneal macrophages. CONCLUSION: Our result suggests that diphenylmethyl selenocyanate has the potential to prevent CP-induced cellular toxicity.

Naphthalimide based novel organoselenocyanates: finding less toxic forms of selenium that would retain protective efficacy.

A series of naphthalimide based organoselenocyanates were synthesized and screened for their toxicity as well as their ability to modulate several detoxifying/antioxidative enzyme levels at a primary screening dose of 3 mg/kg b.w. in normal Swiss albino mice for 30 days. Compound 4d showed highest activity in elevating the detoxifying/antioxidant enzymes levels.

Amelioration of cisplatin-induced nephrotoxicity in mice by oral administration of diphenylmethyl selenocyanate

Abstract Cisplatin is one of the most potent and active cytotoxic drug in the treatment of cancer. However, side-effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the promising efficacy of cisplatin. The present study was designed to ascertain the possible in vivo protective potential of a synthetic organoselenium compound diphenylmethyl selenocyanate (3 mg/kg.b.w.) against the nephrotoxic damage induced by cisplatin (5 mg/kg.b.w. for 5 days) in Swiss albino mice. Treatment with diphenylmethyl selenocyanate markedly reduced cisplatin-induced lipid peroxidation, serum creatinine and blood urea nitrogen levels. Renal antioxidant defense systems, such as glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, catalase, activities and reduced glutathione level, depleted by cisplatin therapy, were restored to normal by the selenium compound. The selenium compound also reduced renal tubular epithelial cell damage, nitric oxide levels and expression of COX-2, and iNOS in kidneys injured by cisplatin. These results demonstrate the protective effect of diphenylmethyl selenocyanate against cisplatin-induced nephrotoxicity in mice.

Influence of novel naphthalimide-based organoselenium on genotoxicity induced by an alkylating agent: the role of reactive oxygen species and selenoenzymes

Abstract Objective The protection conferred by a series of synthetic organoselenium compounds against genotoxicity and oxidative stress induced by a reference mutagen cyclophosphamide (CP) was assessed. Method Genotoxicity was induced in mice by CP treatment (25 mg/kg b.w.) for 10 consecutive days. Organoselenium compounds (3 mg/kg b.w.) were administered orally in a concomitant and pretreatment schedule. DNA damage in peripheral blood lymphocytes and frequency of chromosomal aberration in the bone marrow cells were measured. Liver tissues were collected for analysis of the activity of antioxidant and detoxifying enzymes, lipid peroxidation (LPO) level, glutathione content, and histopathology. Results Exposure to CP not only led to a significant increase in the percent of chromosomal aberration and DNA damage, but also enhanced generation of hepatic reactive oxygen species (ROS) and LPO level. The organoselenium compounds demonstrated marked functional protection against CP-induced genotoxicity. DNA damage and chromosomal aberration along with ROS generation were attenuated in the organoselenium-treated mice compared with the CP-treated control mice. CP caused marked depression in the activities of the selenoenzymes (glutathione peroxidase (GPx) and thioredoxin reductase (TRxR)) and other detoxifying and antioxidant enzymes, while treatment with organoselenium compounds restored all these activities towards normal. Discussion The protective effect of these compounds may be primarily associated with the improvement of the activity of antioxidant and detoxifying enzymes (including the selenoenzymes, GPx, and TRxR) that are known to protect the DNA and other cellular components from oxidative damage.

2-[5-Selenocyanato-pentyl]-6-amino-benzo[de]isoquinoline-1,3-dione inhibits angiogenesis, induces p53 dependent mitochondrial apoptosis and enhances therapeutic efficacy of cyclophosphamide.

The present study embodies a detailed investigation of the chemoenhancement property of a synthetic organoselenium compound, 2-[5-selenocyanato-pentyl]-7-amino benzo[de]isoquinoline-1,3-dione (ANOS) in tumor bearing Swiss albino mice. The results accumulated from this study illustrated that the administration of ANOS significantly potentiated the therapeutic efficacy of cyclophosphamide by reducing the tumor burden and chemotherapy induced toxicity in the host. Ability of ANOS in inducing apoptosis and inhibiting angiogenesis was thought to be the crucial effecter for enhancing the therapeutic efficacy of cyclophosphamide. Fluorescence microscopic study revealed that ANOS was capable of penetrating tumor cells and distributed in the subcellular compartments. We showed that ANOS-induced apoptosis, as evidenced by the TUNEL assay and cleavage of poly(ADP-ribose) polymerase (PARP), involved ROS production and DNA damage in tumor cells. ROS production subsequently activated p53 phosphorylation at Ser-15. This in turn activated cytochrome c (cyt c) release from mitochondria via Bcl-2 and Bax. Finally activation of caspase 3 led to PARP cleavage and apoptosis. These results suggested that p53 dependent mitochondrial pathway was playing an important role in ANOS induced apoptosis of tumor cells. Administration of ANOS also resulted in significant improvement of tumor vasculature and sprouting of the peritoneal cavity along with the normalization of MMP-9 level in serum and ascites fluid of tumor bearing mice. This potential antiangiogenic activity of ANOS also facilitated the therapeutic efficacy of the combination therapy. Furthermore, ANOS significantly suppressed cyclophosphamide-induced liver, hematopoietic and genetic damages. A concomitant decrease in drug-induced toxicity by ANOS might also have enhanced the efficacy of cyclophosphamide by improving the intrinsic defense machineries of the host.

Sensitization of cancer cells to cyclophosphamide therapy by an organoselenium compound through ROS-mediated apoptosis

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.

Dibenz[ a,h ]anthracene

This article is a revision of the previous edition article by William S. Utley, volume 1, pp 790–791,