Rhodamine-123 reduces the dosage of docetaxel necessary to achieve maximal cell growth inhibition in prostate and breast cancer cell lines in vitro Free

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Docetaxel is a taxane class drug approved for the treatment of hormone refractory metastatic prostate cancer and metastatic breast cancer. While docetaxel is effective for extending survival times in patients, severe side effects occur at clinically effective doses. Rhodamine-123 (Rh-123) is a mitochondria-specific vital stain that induces cytotoxicity by interfering with mitochondrial function. Rh-123 has previously been shown to be selectively cytotoxic for prostate cancer cells in vitro and in vivo (Arcadi, J. et al. J. Surg. Oncol., 1995, 59, 86-92.). A Phase I clinical trial with Rh-123 in prostate cancer patients was recently reported (Jones L. W. et al, J Chemother. 2005, 17, 435,). We sought to test whether Rh-123 pre-treatment of cancer cells would enhance the cytotoxicity of docetaxel. In this study, we report results obtained with 3 cell lines grown in vitro: PC 3 and DU145 (prostate cancer) and MDA-MB-231 (breast cancer). Cytotoxcity was assayed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (Mosmann, T. J Immunol Methods.1983, 16, 55-63). Comparisons were made of the dose resulting in half the maximal growth inhibition ([docetaxel]_1/2). In experiments with Rh-123 or docetaxel by themselves, half-maximal cytotoxicity occurred at 1-2µg/ml of Rh-123 and 5-10 µg/ml of docetaxel. In combined treatments, cells were first treated with 2 µg/mL Rh-123 for two days followed by a three day exposure to serial dilutions of docetaxel. In PC3 cells, cells treated only with docetaxel showed a [docetaxel]_1/2 = 5.6 ± 2 ng/mL compared to a [docetaxel]_1/2 = 0.12 ± 0.01 ng/mL for cells pre-treated with Rh-123 (45 times less the dosage necessary for cells treated only with docetaxel). In DU145, the [docetaxel] _1/2 was 7.9 ± 2 ng/mL for docetaxel alone treated cells and [docetaxel]_1/2 was 0.29 ± 0.11 ng/mL for cells pre-treated with Rh-123 (27 times less the dosage necessary for cells treated only with docetaxel). In MDA-MB-231 cells, [docetaxel]_1/2 was 6.2 ± 0.8 ng/mL for docetaxel alone treated cells and [docetaxel]_1/2 was 0.24 ± 0.07 ng/mL for cells pre-treated with Rh-123 (25 times less the dosage necessary for cells treated only with docetaxel). Our study shows Rh-123 pretreatment dramatically reduces the dosage of docetaxel necessary to achieve half-maximal growth inhibition in three different cancer cell lines and suggests the potential for the use of Rh-123 in enhancing docetaxel-based chemotherapy.