Mechanisms of acquired resistance to 2-(4-aminophenyl)benzothiazole (CJM 126, NSC 34445).
2-(4-aminophenyl)benzothiazole (CJM 126) elicits potent growth inhibition in human-derived breast carcinoma cell lines, including oestrogen receptor-positive (ER+) MCF-7wt cells. Analogues substituted in the 3' position with I (DF 129), CH3 (DF 203), or Cl (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-7wt breast cancer cells (IC50 value < 0.001 microM) following long-term exposure to 10 nM or 10 microM CJM 126, MCF-7(10 nM 126) and MCF-7(10 microM 126) respectively, which demonstrate acquired resistance to this agent (IC50 > 30 microM) 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 microM 126 lysates. Significantly decreased depletion of CJM 126 (30 microM) from nutrient medium of MCF-7(10 microM 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 microM) was rapidly depleted from nutrient medium of MCF-7(10 microM 126) culture and accessed nuclei of these cells exerting damage to DNA. The major biotransformation product of CJM 126 in MCF-7(10 microM 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.
Bradshaw
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TD
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, UK.
Chua
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MS
Orr
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Matthews
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CS
Stevens
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MF
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D052160:Benzothiazoles; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C111133:2-(4-aminophenyl)benzothiazole; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D003470:Culture Media; D007527:Isoenzymes; D013844:Thiazoles; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1