Abstract
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 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-7wt breast cancer cells (IC50 value < 0.001 μM) following long-term exposure to 10 nM or 10 μM CJM 126, MCF-710 nM 126 and MCF-710 μM 126 respectively, which demonstrate acquired resistance to this agent (IC50 > 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-710 nM 126 and MCF-710 μM 126 lysates. Significantly decreased depletion of CJM 126 (30 μM) from nutrient medium of MCF-710 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-710 nM 126 cells. In contrast, CJM 126 (30 μM) was rapidly depleted from nutrient medium of MCF-710 μM 126 culture and accessed nuclei of these cells exerting damage to DNA. The major biotransformation product of CJM 126 in MCF-710 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
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References
Akman SA, Forrest G, Chu FF, Esworthy S and Doroshow JH (1990) Antioxidant and xenobiotic-metabolizing enzyme gene expression in doxorubicin-resistant human breast cancer cells. Cancer Res 50: 1397–1402
Batist G, Tulpules A, Sinha BK, Katki AG, Myers CE and Cowan KH (1986) Overexpression of a novel anionic glutathione transferase in multi-drug resistant human breast cancer cells. J Biol Chem 261: 15544–15549
Birnboim HC and Jevcak JJ (1981) Fluorometric method for rapid detection of DNA strand breaks in human white blood cells produced by low doses of radiation. Cancer Res 41: 1889–1892
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254
Bradshaw TD, Wrigley S, Shi D-F, Schultz RJ, Paull KD and Stevens MFG 1998 a) 2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro antitumour activity. Br J Cancer 77: 745–752
Bradshaw TD, Shi D-F, Schultz RJ, Paull KD, Kelland L, Wilson A, Garner C, Fiebig HH, Wrigley S and Stevens MFG 1998 b) Influence of 2-(4-aminophenyl)benzothiazoles on growth of human ovarian carcinoma cells in vitro and in vivo. Br J Cancer 78: 421–429
Caruso JA and Batist G (2000) Divergent mechanisms for loss of Ah-responsiveness in benzo[a]pyrene- and adriamycin-resistant MCF-7 cells. Biochem Pharmacol 57: 1253–1263
Chua M-S, Shi D-F, Wrigley S, Bradshaw TD, Hutchinson I, Shaw PN, Barrett DA, Stanley L, Sausville EA and Stevens MFG (2000) Antitumour Benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl)benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines. J Med Chem 42: 381–392
Chua M-S, Kashiyama E, Bradshaw TD, Stinson SF, Brantley E, Sausville EA and Stevens MFG Role of CYPIAI in modulation of antitumour properties of the novel agent 2-(4-amino-3-methyl-phenyl) benzothiazole (DF 203, NSC 674495) in human breast cancer cells. Cancer Research (submitted)
Crofts FG, Sutter TR and Strickland PT (1998) Metabolism of 2-amino-1-methyl-6-phenylimdazo [4, 5-6] pyridine by human cytochrome P45501A1, P4501A2 and P4501B1. Carcinogenesis 19: 1969–1973
Hayes JD and Wolf CR (1990) Molecular mechanisms of drug resistance. Biochem J 272: 281–295
Ivy SP, Tulpule A, Fairchild CR, Averbuch SD, Myers CE, Nebert DW, Baird WM and Cowan KH (1988) Altered regulation of P-4501A1 expression in a multidrug-resistant MCF-7 human breast cancer cell line. J Biol Chem 263: 19119–19125
Kashiyama E, Hutchinson I, Chua M-S, Stinson SF, Phillips LR, Kaur G, Sausville EA, Bradshaw TD, Westwell AD and Stevens MFG (2000) Antitumor benzothiazoles 8. Synthesis, metabolic formation and biological properties of antitumor 2-(4-aminophenyl)benzothiazoles. J Med Chem 42: 4172–4184
Kinzler KW and Vogelstein B (1994) Clinical implications of basic research: Cancer therapy meets p53. New Engl J Med 331: 49–50
Kress S and Greenlee WF (1997) Cell-specific regulation of human CYP1A1 and CYP1B1 genes. Cancer Res 57: 1264–1269
Malcomson RDG, Oren M, Wyllie AH and Harrison DJ (1995) p53-Independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs. Br J Cancer 72: 952–957
Pastrakuljic A, Tang BK, Roberts EA and Kalow W (1997) Distinction of CYP1A1 and CYP1A2 activity by selective inhibition using fluvoxamine and isosafrole. Biochem Pharmacol 53: 531–538
Pelkonen O and Raunio H (1997) Metabolic activation of toxins: tissue-specific expression and metabolism in target organs. Env Health Perspectives 105: 767–774
Sadrieh N, Davis CD and Snyderwine EG (1996) N -acetyltransferase expression and metabolic activation of the food-derived heterocyclic amines in the human mammary gland. Cancer Res 56: 2683–2687
Shi DF, Bradshaw TD, Wrigley S, McCall CJ, Lelieveld P, Fichtner I and Stevens MFG (1996) Antitumour benzothiazoles. 3. Synthesis of 2-(4-aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo. J Med Chem 37: 3375–3384
Sinha BK, Katki AG, Batist G, Cowan KH and Myers CE (1987) Differential formation of hydroxyl radicals by adriamycin in sensitive and resistant MCF-7 human breast tumour cells: Implications for the mechanism of action. Biochem 26: 3776–3781
Stacey M, Thygesen P, Stanley L, Matas N, Risch A and Sim E (1996) Arylamine N -acetyltransferase as a potential biomarker in bladder cancer: fluorescent in situ hybridization and immunohistochemistry studies. Biomarkers 1: 55–61
Stevens MFG, McCall CJ, Lelieveld P, Alexander P, Richter A and Davies DE (1994) Structural studies on bioactive compounds. 23. Synthesis of polyhydroxylated 2-phenylbenzothiazoles and a comparison of their cytotoxicities and pharmacological properties with genistein and quercetin. J Med Chem 37: 1689–1695
Weinstein JR, Myers TG, O’Connor PM, Friend SH, Fornace AJF, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, Vanosdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE and Paull KD (1997) An information-intensive approach to the molecular pharmacology of cancer. Science 275: 343–349
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Bradshaw, T., Chua, MS., Orr, S. et al. Mechanisms of acquired resistance to 2-(4-aminophenyl)benzothiazole (CJM 126, NSC 34445). Br J Cancer 83, 270–277 (2000). https://doi.org/10.1054/bjoc.2000.1231
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DOI: https://doi.org/10.1054/bjoc.2000.1231
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