Tetramethylpiperidine-Substituted Phenazines Inhibit the Proliferation of Intrinsically Multidrug Resistant Carcinoma Cell Lines

Authors: van Niekerk E.1; O'Sullivan J.F.2; Jooné G.K.3; van Rensburg C.E.J.3

Source: Investigational New Drugs, Volume 19, Number 3, August 2001 , pp. 211-217(7)

Publisher: Springer

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Abstract:

The effects of nine new tetramethylpiperidine (TMP)-substituted phenazines on the growth of a human esophageal cancer cell line (WHCO_3), two human hepatocellular carcinoma cell lines (PLC and HepG2) and three human colon cancer cell lines (CaCo_2, COLO 320DM and HT29) were compared to those of clofazimine, B669 and five standard chemotherapeutic agents. The three most active TMP-substituted phenazines against these cell lines were B3962, B4126 and B4125 with mean IC_50 values for all the cancer cell lines tested of 0.36, 0.47 and 0.48 mug/ml respectively. B3962 and B4126, but not B4125 were also the most active against a semi-continuous human fibroblast culture (MRC5). The compound with the highest tumor specificity relative to the fibroblast culture, was B4125. Importantly, there was minimal variation in sensitivity of the different cell lines, including a multidrug resistant cell line (COLO 320DM) expressing high levels of P-glycoprotein, to the TMP-substituted phenazines. This was not the case with the standard chemotherapeutic agents. The efficacy of compounds such as B4125 against a broad spectrum of multidrug resistant cancer cell lines, together with their relatively high tumor specificity, suggests that these agents may be useful in the treatment of intrinsically resistant cancers such as colon and liver cancer.

Keywords: phenazines; multidrug resistant

Language: English

Document Type: Regular paper

Affiliations: 1: Department of Internal Medicine, Faculty of Medicine, University of Pretoria, Pretoria, South Africa 2: Department of Chemistry, University College Dublin, Belfield, Republic of Ireland 3: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Institute for Pathology, Faculty of Medicine, University of Pretoria, Pretoria, South Africa

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