title: IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells.
abstract: Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline, exhibited more than ten-fold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and sub-micromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and five-fold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer.
authors.affiliation: School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal 462033, MP, India.
authors.forename: Chandrabose
authors.initials: C
authors.lastname: Karthikeyan
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, CVMNAH, Tuskegee University, Tuskegee, AL 36088, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, CVMNAH, Tuskegee University, Tuskegee, AL 36088, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Moore
authors.affiliation: Pediatric Gastroenterology and Nutrition, Oklahoma State University, Oklahoma City, OK 73104, USA.
authors.forename: Roopali
authors.initials: R
authors.lastname: Mittal
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Suswam
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Kodye L
authors.initials: KL
authors.lastname: Abbott
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
authors.forename: Satyanarayana R
authors.initials: SR
authors.lastname: Pondugula
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Upender
authors.initials: U
authors.lastname: Manne
authors.affiliation: New York University School of Medicine, New York, NY, USA.
authors.forename: Narayanan K
authors.initials: NK
authors.lastname: Narayanan
authors.affiliation: School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal 462033, MP, India. Electronic address: piyush.trivedi@rgtu.net.
authors.forename: Piyush
authors.initials: P
authors.lastname: Trivedi
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, CVMNAH, Tuskegee University, Tuskegee, AL 36088, USA. Electronic address: atiwari@mytu.tuskegee.edu.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004285:Dogs; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011804:Quinolines
keywords: Anticancer drugs; Drug resistance; New drug development; Plant analogues