title: A novel colchicine-based microtubule inhibitor exhibits potent antitumor activity by inducing mitochondrial mediated apoptosis in MIA PaCa-2 pancreatic cancer cells.
abstract: Colchicine, an antimitotic alkaloid isolated from Colchicum autumnale, is a classical drug for treatment of gout and familial Mediterranean fever. It causes antiproliferative effects through the inhibition of microtubule formation, which leads to mitotic arrest and cell death by apoptosis. Here, we report that a novel colchicine analog, 4o (N-[(7S)-1,2,3-trimethoxy-9-oxo-10-[3-(trifluoromethyl)-4-chlorophenylamino]-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide), which exhibited potent anticancer activities both in vitro and in vivo. In this study, 4o with excellent pharmacokinetic profile and no P-gp induction liability displayed strong inhibition of proliferation against various human cancer cell lines. However, pancreatic cancer cell line MIA PaCa-2 was found to be more sensitive towards 4o and showed strong inhibition in concentration and time-dependent manner. By increasing intracellular reactive oxygen species (ROS) levels, 4o induced endoplasmic reticular stress and mitochondrial dysfunction in MIA PaCa-2 cells. Blockage of ROS production reversed 4o-induced endoplasmic reticulum (ER) stress, calcium release, and cell death. More importantly, it revealed that increased ROS generation might be an effective strategy in treating human pancreatic cancer. Further 4o treatment induced mitotic arrest, altered the expression of cell cycle-associated proteins, and disrupted the microtubules in MIA PaCa-2 cells. 4o treatment caused loss of mitochondrial membrane potential, cytochrome c release, upregulation of Bax, downregulation of Bcl-2, and cleavage of caspase-3, thereby showing activation of mitochondrial mediated apoptosis. The in vivo anticancer activity of the compound was studied using sarcoma-180 (ascitic) and leukemia (P388 lymphocytic and L1210 lymphoid) models in mice and showed promising antitumor activity with the least toxicity unlike colchicine. Such studies have hitherto not been reported. Taken together, these findings highlighted that 4o, a potent derivative of colchicine, causes tumor regression with reduced toxicity and provides a novel anticancer candidate for the therapeutic use.
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.|Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.|Natural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Baljinder
authors.initials: B
authors.lastname: Singh
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Mahajan
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India. prsharma@iiim.ac.in.|Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India. prsharma@iiim.ac.in.
authors.forename: Parduman R
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.|Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India.
authors.forename: Mubashir J
authors.initials: MJ
authors.lastname: Mintoo
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India. dmmondhe@iiim.res.in.|Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India. dmmondhe@iiim.res.in.
authors.forename: Dilip M
authors.initials: DM
authors.lastname: Mondhe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D050257:Tubulin Modulators / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D050257:Tubulin Modulators; D003078:Colchicine
keywords: Apoptosis; Colchicine analog; Cytotoxicity; Reactive oxygen species; Tubulin