title: Acetylamine derivative of diospyrin, a plant-derived binaphthylquinonoid, inhibits human colon cancer growth in Nod-Scid mice.
abstract: Anticancer activity of diospyrin and its derivatives (1-5) was evaluated against thirteen human cell lines. Compared to diospyrin (1), the acetylamine derivative (4) exhibited increase in cytotoxicity, particularly in HT-29 colon cancer cells, showing GI50 values of 33.90 and 1.96 μM, respectively. Also, enhanced toxicity was observed when cells, pre-treated with compound 4, were exposed to radiation. In vivo assessment of 4 was undertaken on tumour-bearing Nod-Scid mice treated at 4 mg/kg/day. Significant reduction in relative tumour volume (~86-91 %) was observed during the 12th-37th days after drug treatment. Increased caspase-3 activity and DNA ladder formation was observed in HT-29 cells after treatment with 4, suggesting induction of apoptotic death after drug treatment. Moreover, flow cytometric determination of Annexin V- FITC positive and PI negative cells demonstrated 17.4, 26.4, and 27.9 % of early apoptosis, respectively, upon treatment with 5, 10 and 25 μM of 4. HT-29 cells after treatment with 4 (1-25 μM) revealed ~2.5- 3- folds generation of ROS. Furthermore, concentration dependent decrease of mitochondrial trans-membrane potential (∆ψm), and expression of Bcl-2/Bax and other marker proteins suggested involvement of mitochondrial pathway of cell death. Overall, our results demonstrated the underlying cell-death mechanism of the plant-derived naphthoquinonoid (4), and established it as a prospective chemotherapeutic 'lead' molecule against colon cancer.
authors.affiliation: Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Hazra
authors.forename: Subhalakshmi
authors.initials: S
authors.lastname: Ghosh
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: B N
authors.initials: BN
authors.lastname: Pandey
authors.forename: Banasri
authors.initials: B
authors.lastname: Hazra
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053938:DNA Fragmentation; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009285:Naphthoquinones; D053148:Caspase 3; C043546:diospyrin