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
Autor: | Piyush Trivedi, Narayanan K. Narayanan, Esther A. Suswam, Crystal Lee, Satyanarayana R. Pondugula, Joshua Moore, Kodye L. Abbott, Chandrabose Karthikeyan, Roopali Mittal, Amit K. Tiwari, Upender Manne |
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Rok vydání: | 2014 |
Předmět: |
Abcg2
Colorectal cancer Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Apoptosis Pharmacology Biochemistry Article Madin Darby Canine Kidney Cells Mice Dogs Drug Discovery medicine Cytotoxic T cell Animals Humans Cytotoxicity Molecular Biology biology Chemistry Organic Chemistry HEK 293 cells Cancer Hep G2 Cells medicine.disease HCT116 Cells Drug Resistance Multiple HEK293 Cells Pyrimidines Drug Resistance Neoplasm Cancer cell Colonic Neoplasms Cancer research biology.protein MCF-7 Cells Quinolines Molecular Medicine Drug Screening Assays Antitumor |
Zdroj: | Bioorganicmedicinal chemistry. 23(3) |
ISSN: | 1464-3391 |
Popis: | 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. |
Databáze: | OpenAIRE |
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