title: Selective Pro-Apoptotic Activity of Novel 3,3'-(Aryl/Alkyl-Methylene)Bis(2-Hydroxynaphthalene-1,4-Dione) Derivatives on Human Cancer Cells via the Induction Reactive Oxygen Species.
abstract: Selective induction of apoptosis in cancer cells barring the normal cells is considered as an effective strategy to combat cancer. In the present study, a series of twenty-two (22) synthetic 3,3'-(aryl/alkyl-methylene)bis(2-hydroxynaphthalene-1,4-dione) bis-lawsone derivatives were assayed for their pro-apoptotic activity in six different cell lines (five cancerous and one normal) using MTT assay. Out of these 22 test compounds, 1j was found to be the most effective in inducing apoptosis in human glioma cells (CCF-4) among the different cell lines used in the study. The activity of this compound, 1j, was then compared to a popular anticancer drug, cisplatin, having limited usage because of its nephrotoxic nature. In this study, 1j derivative showed much less toxicity to the normal kidney cells compared to cisplatin, thus indicating the superiority of 1j as a possible anticancer agent. This compound was observed to induce apoptosis in the glioma cells by inducing the caspase dependent apoptotic pathways via ROS and downregulating the PI3K/AKT/mTOR pathway. Estimation of different oxidative stress markers also confirms the induction of oxidative stress in 1j exposed cancer cells. The toxicity of 1j compound toward cancer cells was confirmed further by different flow cytometrical analyses to estimate the mitochondrial membrane potential and cell cycle. The sensitivity of malignant cells to apoptosis, provoked by this synthetic derivative in vitro, deserves further studies in suitable in vivo models. These studies not only identified a novel anticancer drug candidate but also help to understand the metabolism of ROS and its application in cancer treatment.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
authors.forename: Pritam
authors.initials: P
authors.lastname: Sadhukhan
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Saha
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Sinha
authors.affiliation: Laboratory of Natural Products & Organic Synthesis, Department of Chemistry, Visva-Bharati (a Central University), Santiniketan, 731235, West Bengal, India.
authors.forename: Goutam
authors.initials: G
authors.lastname: Brahmachari
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India.
authors.forename: Parames C
authors.initials: PC
authors.lastname: Sil
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D002945:Cisplatin; D009281:Naphthalenes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases