In vitro and in vivo anticancer potential and molecular targets of the new colchicine analog IIIM-067.

Autor: Malik S; Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India., Mintoo MJ; Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India., Reddy CN; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India., Kumar R; Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India., Kotwal P; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India; Pharmacokinetics-Pharmacodynamics (PK-PD), Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India., Bharate SB; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India; Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India., Nandi U; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India; Pharmacokinetics-Pharmacodynamics (PK-PD), Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India., Mondhe DM; Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India. Electronic address: mondhe33@gmail.com., Shukla SK; Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu 180001, Jammu & Kashmir, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India. Electronic address: sanket.shukla@iiim.res.in.
Jazyk: angličtina
Zdroj: Journal of integrative medicine [J Integr Med] 2023 Jan; Vol. 21 (1), pp. 62-76. Date of Electronic Publication: 2022 Sep 30.
DOI: 10.1016/j.joim.2022.09.006
Abstrakt: Objective: The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells.
Methods: Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were observed using fluorescence microscopy. Western blot analysis was used to quantify expression of proteins involved in apoptosis, cell cycle, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Pharmacokinetic and in vivo efficacy studies against Ehrlich ascites carcinoma (EAC) and Ehrlich solid tumor models were conducted using Swiss albino mice.
Results: IIIM-067 showed potent cytotoxicity and better selectivity than all other colchicine analogs screened in this study. The selective activity of IIIM-067 toward A549 cells was higher among other cancer cell lines, with a selectivity index (SI) value of 2.28. IIIM-067 demonstrated concentration- and time-dependent cytotoxicity against A549 cells with half-maximal inhibitory concentration values of 0.207, 0.150 and 0.106 μmol/L at 24, 48 and 72 h, respectively. It also had reduced toxicity to normal cells (SI > 1) than the parent compound colchicine (SI = 1). IIIM-067 reduced the clonogenic ability of A549 cells in a dose-dependent manner. IIIM-067 enhanced ROS production from 24.6% at 0.05 μmol/L to 82.1% at 0.4 μmol/L and substantially decreased the MMP (100% in control to 5.6% at 0.4 μmol/L). The annexin V-FITC assay demonstrated 78% apoptosis at 0.4 μmol/L. IIIM-067 significantly (P < 0.5) induced the expression of various intrinsic apoptotic pathway proteins, and it differentially regulated the PI3K/AKT/mTOR signaling pathway. Furthermore, IIIM-067 exhibited remarkable in vivo anticancer activity against the murine EAC model, with tumor growth inhibition (TGI) of 67.0% at a dose of 6 mg/kg (i.p.) and a reduced mortality compared to colchicine. IIIM-067 also effectively inhibited the tumor growth in the murine solid tumor model with TGI rates of 48.10%, 55.68% and 44.00% at doses of 5 mg/kg (i.p.), 6 mg/kg (i.p.) and 7 mg/kg (p.o.), respectively.
Conclusion: IIIM-067 exhibited significant anticancer activity with reduced toxicity both in vitro and in vivo and is a promising anticancer candidate. However, further studies are required in clinical settings to fully understand its potential.
(Copyright © 2022 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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