CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance

Abstract

The cytochrome P450 CYP1B1 is consistently overexpressed in tumour cells as compared to their normal counterparts, but its precise role in drug resistance is yet to be defined. It has been reported that transfection of CYP1B1 results in increased resistance to docetaxel in V79 cells (McFadyen et al, 2001). In this study, we analysed changes in expression of CYP1B1 mRNA associated with pulse selection of MCF-7 cells with docetaxel. Docetaxel-selected MCF-7 cells (MCF-7 Txt), which showed increased resistance to this drug as compared to parental MCF-7 cells, showed a noteworthy increase in CYP1B1 mRNA expression, paralleled by increased ethoxyresorufin-O-deethylase (EROD) activity levels. This effect was not observed in cisplatin-or adriamycin-selected MCF-7 cells, or in docetaxel-selected colon, lung or pancreatic carcinoma cells. Short-term treatment with docetaxel induced CYP1B1 mRNA expression in MDA 453 and BT-20 breast carcinoma cells, but not in MCF-7 cells. Transfection of MCF-7 Txt cells with CYP1B1 siRNA did not significantly affect docetaxel-induced toxicity, but it decreased cell survival in the absence of drug. Preincubation of docetaxel with recombinant CYP1B1 did not affect drug toxicity in A549 cells. These results suggest that CYP1B1 does not directly inactivate docetaxel, but rather might promote cell survival in MCF-7 Txt cells, providing an explanation for its association with drug resistance. British Journal of Cancer (2008) Breast cancer affects a significant number of women worldwide and is a leading cause of cancer deaths (Chintamani et al, 2004). Current therapies for breast cancer include locoregional (surgical) treatment, anti-hormone therapy, radiotherapy and chemotherapy (O'Driscoll and Clynes, 2006). Chemotherapeutic treatment of breast cancer, although of great importance in the management of the disease, has limited benefits for many patients due to intrinsic or acquired resistance to the effects of anticancer drugs. Moreover, chemoresistance is often associated with a more aggressive phenotype with an increased tendency to invade and metastasise (Campbell et al, 2001).Cytochromes P450 are a family of enzymes implicated in the biotransformation of both xenobiotics and endogenous compounds. Their primary functions are the synthesis of steroids and bile acids and the detoxification of many foreign substances, such as drugs and environmental agents.CYP1B1 is the only member of the CYP1B subfamily; it catalyses the hydroxylation of 17-b-oestradiol at the C4 position (Jefcoate et al, 2000) and is involved in testosterone biotransformation as well (Shimada et al, 1999). It is also known to metabolise xenobiotics such as ethoxyresorufin, theophylline and caffeine (Shimada et al, 1997). CYP1B1 is constitutively expressed at the mRNA level in mammal steroidogenic tissues, such as rat granulosa cells (Dasmahapatra et al, 2002) and its expression can be induced in these and other tissues by peptide hormones, cAMP and ligands of the aryl hydrocarbon receptor (AhR). Crosstalk has been described...

A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate

“…The role of CYP1B1 in tumour suppression was also shown in a study where CYP1B1 null mice were protected against DMBA-induced tumours as compared with their wild-type counterparts (Buters et al, 1999). As CYP1B1 can inactivate the prostate cancer dug flutamide (Rochat et al, 2001) and is also induced in breast cancer cells after treatment with docetaxel (Martinez et al, 2008), it may have an important function in the development of resistance to chemotherapy. Overall, CYP1B1 has a variety of functions in both the treatment and development of breast cancer.…”

Gene expression profiling of the androgen independent prostate cancer cells demonstrates complex mechanisms mediating resistance to docetaxel

“…We at first studied three relatively under-characterized genes identified in previous studies as potentially pertinent to docetaxel resistance. These included cytochrome P450 CYP1B1 that was shown to improve ability in cell survival in docetaxel resistant MCF-7 breast cancer cells 4 and was strongly induced by docetaxel in resistant PC-3 cells. We also reasoned that the persistent upregulation of Cyclin G 2 , the only cell cycle related gene detected in the docetaxel resistant PC-3 derivatives, might be also relevant to docetaxel resistance.…”

“…12 However CYP1B1 does not directly inactivate docetaxel and rather promotes cell survival. 4 Other studies determined that docetaxel was not metabolized by recombinant human CYP1B1 but binds to CYP1B1 to act as an effector of this enzyme. 13 Because shCYP1B1 silencing in 8B2 cells did not lead to measurable reduction in docetaxel resistance we concluded that CYP1B1 was not a key mediator of docetaxel resistance in our experimental model.…”

ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category

“…Within this subset, we compared 26 ASXL1-mut to 39 ASXL1-wt patients and identified a signature of 92 differentially expressed probe sets, corresponding to 67 named genes (supplemental Table 4). Among the genes most strongly up-regulated in ASXL1-mut patients were LRP6 (a WNT signaling pathway coreceptor 30 ), cytochrome P450 CYP1B1 (associated with chemotherapy resistance 31 ), and gap junction protein ␣ 1 (GJA1, connexin 43). GJA1 couples early hematopoietic and stromal cells in the BM, is important for regeneration of hematopoiesis after chemotherapy, 32 and mediates secretion of stroma-derived factor 1 (CXCL12), a chemokine essential for hematopoietic stem cell homing and function.…”