Abstract
A newly designed organoselenium compound, methyl substituted umbelliferone selenocyanate (MUS), was synthesized as a primary hit against the myelotoxic activity of carboplatin. MUS was administered at 6 mg/kg b.wt, p.o. in concomitant and pretreatment schedules with carboplatin (12 mg/kg b.wt, i.p. for 10 days) in female Swiss albino mouse. MUS treatment reduced (P < 0.001) the percentage of chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in murine bone marrow cells and also enhanced (P < 0.001) the bone marrow cell proliferation of the carboplatin-treated mice. These activities cumulatively restored the viable bone marrow cell count towards normalcy. Myeloprotection by MUS was achieved, in part, due to a significant reduction in the ROS/RNS formation and restoration of glutathione redox pool. Additionally, MUS synergistically enhanced the cytotoxicity of carboplatin against two human cancer cell lines (MCF-7 and Colo-205). Furthermore, MUS can effectively potentiate the antitumour activity of carboplatin against two murine cancers (Dalton’s Lymphoma and Sarcoma-180) in vivo. These preclinical findings clearly indicate that MUS can improve the therapeutic index of carboplatin and ensures more effective therapeutic strategy against cancer for clinical development.
Highlights
Despite much advancement in targeted and customized cancer chemotherapy, platinum-based drugs are in routine clinical use in low and middle-income countries
methyl substituted umbelliferone selenocyanate (MUS) at its most effective dose were evaluated for its chemoprotective potential against CBDCA-induced myelotoxicity in bone marrow cells of Swiss albino mouse
The results revealed that MUS augmented the cytotoxicity of CBDCA in both the ascites tumour models of Dalton’s Lymphoma (DAL) and S-180
Summary
Despite much advancement in targeted and customized cancer chemotherapy, platinum-based drugs are in routine clinical use in low and middle-income countries. This leads to increases in replication error and eventually generates mutation In this scenario, protection from CBDCA-induced myelotoxicity without compromising its chemotherapeutic efficacy is a clinical necessity. Some biochemical properties of selenium like its (a) incorporation into proteins as selenocysteine and selenomethionine during translation, (b) presence of the functional moiety of 25 selenoenzyme in human[10,11] and (c) dual behavior to act as antioxidant and pro-oxidant depending upon cellular redox environment make it unique among other possible candidates. MUS at its most effective dose were evaluated for its chemoprotective potential against CBDCA-induced myelotoxicity in bone marrow cells of Swiss albino mouse. In vitro therapeutic efficacy was evaluated against MCF-7 and Colo-205 whereas in vivo study was carried out in Swiss albino mice bearing Dalton’s Lymphoma or Sarcoma-180 in solid as well as ascites tumour forms
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