Abstract
Escalating incidences of cancer, especially in developed and developing countries, demand evaluation of potential unexplored natural drug resources. Here, anticancer potential of 9-Ethyliminomethyl-12-(morpholin-4-ylmethoxy)-5,8,13,16-tetraaza -hexacene-2,3-dicarboxylic acid (EMTAHDCA) isolated from fresh water cyanobacterium Nostoc sp. MGL001 was screened through in silico, in vitro, and in vivo studies. For in silico analysis, EMTAHDCA was selected as ligand and 11 cancer related proteins (Protein Data Bank ID: 1BIX, 1NOW, 1TE6, 2RCW, 2UVL, 2VCJ, 3CRY, 3HQU, 3NMQ, 5P21, and 4B7P) which are common targets of various anticancer drugs were selected as receptors. The results obtained from in silico analysis showed that EMTAHDCA has strong binding affinity for all the 11 target protein receptors. The ability of EMTAHDCA to bind active sites of cancer protein targets indicated that it is functionally similar to commercially available anticancer drugs. For assessing cellular metabolic activities, in vitro studies were performed by using calorimetric assay viz. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT). Results showed that EMTAHDCA induced significant cytotoxic response against Dalton's lymphoma ascites (DLA) cells in a dose and time dependent manner with an inhibitory concentration (IC50) value of 372.4 ng/mL after 24 h of incubation. However, in case of normal bone marrow cells, the EMTAHDCA did not induce cytotoxicity as the IC50 value was not obtained even with higher dose of 1,000 ng/mL EMTAHDCA. Further, in vivo studies revealed that the median life span/survival days of tumor bearing mice treated with EMTAHDCA increased significantly with a fold change of ~1.9 and 1.81 corresponding to doses of 5 and 10 mg/kg body weight (B.W.) of EMTAHDCA respectively, as compared to the DL group. Our results suggest that 5 mg/kg B.W. is effective since the dose of 10 mg/kg B.W. did not show any significant difference as compared to 5 mg/kg B.W. Taken together, our findings based on in silico, in vitro, and in vivo analyses suggest that EMTAHDCA has potential anticancer effects, and thus, can be considered for cancer treatment.
Highlights
Cancer is one of the world’s deadliest diseases and is becoming a matter of worldwide concern
Molecular docking was successfully performed between the selected ligand (EMTAHDCA) and 11 cancer protein targets (PDB ID: 1BIX, 1NOW, 1TE6, 2RCW, 2UVL, 2VCJ, 3CRY, 3HQU, 3NMQ, 5P21, and 4B7P; Table S1) using Yet Another Scientific Artificial Reality Application (YASARA) software
EMTAHDCA efficiently interacted with the cancer target 2VCJ with a good binding energy of 8.5 and less dissociation constant of 567576.2
Summary
Cancer is one of the world’s deadliest diseases and is becoming a matter of worldwide concern. Escalating cancer evidences, ineffectiveness of anticancer drugs, and adverse side-effects of drug over-dose demand more investigations on identifying newer, broad-spectrum anticancer molecules from less explored, potential natural products. Over the past few years, natural products and their derivatives have been recognized as important sources of new medicines and therapeutic agents (Cragg and Newman, 2013). Actinomycetes, fungi, and bacteria including cyanobacteria are known for producing bioactive metabolites (Bérdy, 2005; El-Elimat et al, 2012). Of these organisms, cyanobacterial cultivation without organic substrates is considered as a cost effective approach for scientific studies as compared to other microorganisms (Bullerjahn and Post, 2014; Dias et al, 2015)
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