Mechanisms of acquired resistance to 2-(4-aminophenyl)benzothiazole (CJM 126, NSC 34445)

Abstract

2-(4-aminophenyl)benzothiazole (CJM 126) elicits potent growth inhibition in human-derived breast carcinoma cell lines, including oestrogen receptor-positive (ER+) MCF-7 wt cells. Analogues substituted in the 3′ position with I (DF 129), CH 3 (DF 203), or CI (DF 229) possess an extended profile of antitumour activity with remarkable selective activity in cell lines derived from solid tumours associated with poor prognosis, e.g. breast, ovarian, renal and colon. Growth inhibition occurs via unknown, possibly novel mechanism(s) of action. Two cell lines have been derived from sensitive MCF-7 wt breast cancer cells (IC 50 value < 0.001 μM) following long-term exposure to 10 nM or 10 μM CJM 126, MCF-7 10 μM 126 and MCF-7 10 μM 126 respectively, which demonstrate acquired resistance to this agent (IC 50 > 30 μM) and cross-resistance to DF 129, DF 203 and DF 229. Sensitivity to tamoxifen, benzo[a]pyrene (BP), mitomyin C, doxorubicin and actinomycin D is retained. Resistance may, in part, be conferred by the constitutively increased expression of bcl-2 and p53 proteins detected in MCF-7 10 nM 126 and MCF-7 10 μM 126 lysates. Significantly decreased depletion of CJM 126 (30 μM) from nutrient medium of MCF-7 10 nM 126 cells was observed with predominantly cytoplasmic drug localization and negligible DNA strand breaks. N -acetyl transferase (NAT)1 and NAT2 proteins were expressed by all three MCF-7 sub-lines, but significantly higher expression of NAT2 was accompanied by enhanced acetylation efficacy in MCF-7 10 nM 126 cells. In contrast, CJM 126 (30 μM) was rapidly depleted from nutrient medium of MCF-7 10 μM 126 culture and accessed nuclei of these cells exerting damage to DNA. The major biotransformation product of CJM 126 in MCF-7 10 μM 126 cells was 2-(4-aminophenyl)-6-hydroxybenzothiazole (6-OH 126). This metabolite possessed no antitumour activity. Accordingly, in this sub-line, low constitutive expression and activity of cytochrome P450 (CYP) 1A1 was detected. © 2000 Cancer Research Campaign

Benzothiazoles: How Relevant in Cancer Drug Design Strategy?

“…The details of the reported data with the corresponding references are provided in the Table 1 [33][34][35][36][37][38][39][40][41][42][43][44]. The importance of some structural features can be evaluated on the basis of reported compounds which show diversity for those structural elements.…”

2-(4-Aminophenyl) Benzothiazole: A Potent and Selective Pharmacophore with Novel Mechanistic Action Towards Various Tumour Cell Lines

“…In vitro unique and remarkable selectivity and characteristic pattern of benzothiazole is confirmed by National Cancer Institute (NCI) [1,5,6]. These agents have potent and selective activity mainly towards MCF-7 cells (including oestrogen receptor ER+ MCF-7 cells [7] and ER-cells [8]), MDA-435, MDA-MB-468 cells.…”

“…2) and secondly, by the reaction of 2-aminothiophenol with substituted benzoic acid (in presence of polyphosporic acid at 220 o C) [7], (Fig. 3).…”

“…4) Replacement of 2-(4 amino phenyl) group of lead compound with 2-(pyridin-4-yl) or 2-(2-aminopyridin-5-yl) residue results in a compound having cytotoxicity only at concentration >1µM. Introduction of bromo group to give 2-(2-amino-3-bromo pyridine-5-yl) benzothiazole (Table 1 (3, 4 and 5)) enhances activity >100 fold over unbrominated amino pyridine but potency is still considerably less than that of bromo aryl amine [7,9]. The primary aromatic amine has been derivatized as amino acid amides, by conjugating ( Fig.…”

Deciphering the role of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer cell metabolism using a systems biology approach.

“…In addition, NAT2 mRNA has been detected in MCF-7 breast cancer cells at very low levels 96 ; however, NAT1 was not measured at the same time preventing a direct comparison of expression between the two isozymes. Bradshaw et al detected NAT1 and NAT2 by western blotting in the ER-positive breast cancer cell line MCF-7; however, the expression levels were not compared between the two proteins 101 . Based on limited data, it has been hypothesized that NAT2 expression is very low in breast tissue and negligible in comparison to NAT1 expression.…”