Induction of 1C aldoketoreductases and other drug dose-dependent genes upon acquisition of anthracycline resistance

Abstract

Taken together, we show for the first time that a variety of genes (particularly redox genes such as AKR1C2 and AKR1C3) can be temporally and causally correlated with the acquisition of anthracycline resistance in breast tumor cells.

Identification of Aldo-Keto Reductase AKR1B10 as a Selective Target for Modification and Inhibition by Prostaglandin A1: Implications for Antitumoral Activity

“…We have also observed that AKR inhibition in A549 cells is associated with an improvement of the effects of doxorubicin, a widely used drug in the therapy of lung (46) and other cancers (47). Doxorubicin clinical efficacy, however, is limited by the development of cancer cell resistance due to induction of drug detoxification mechanisms, including conversion by AKR enzymes to the less effective metabolite doxorubicinol (37). It should be noted that although most studies on doxorubicin action have been conducted with micromolar concentrations, the effects herein reported occur at nanomolar doxorubicin concentrations.…”

“…6B), thus suggesting an inhibition of tumorigenic potential. AKR1B10 is involved in the metabolism of a variety of anticancer compounds, including doxorubicin and daunorubicin, potentially leading to chemoresistance (32,37). Therefore, we explored whether PGA 1 could improve doxorubicin efficiency.…”

The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acquisition of drug resistance

“…This study used a unique panel of progressively drug-resistant breast tumor cells to assess the temporal and causal relationships between exposure to specific chemotherapeutics, changes in ABCB1 promoter methylation and acquisition of drug resistance. We have previously shown that a specific threshold drug dose must be reached in order to acquire drug resistance and that multiple molecular mechanisms appear to be associated with the acquisition of drug resistance, including decreased drug accumulation through overexpression of the Abcb1 drug transporter in MCF-7 EPI and MCF-7 TAX-2 cells 13,14 (unpublished observations). We first examined the possibilities that differences in ABCB1 gene amplification, ABCB1 transcript stability or ABCB1 mRNA translation may account for the higher Heat-shock-like element À99 to À66 None 34 a Adjacent CpG site near to the element.…”

“…Analysis of the cell lines revealed that a specific 'threshold' selection dose (dose-9) had to be reached before any resistance to chemotherapy drugs was observed (31.5 nM epirubicin, 29.1 nM doxorubicin, 3.66 nM paclitaxel). Furthermore, acquisition of drug resistance involved multiple changes in gene expression, 14 including upregulation of ABCB1 expression in MCF-7 EPI and MCF-7 TAX-2 cells (but not in MCF-7 DOX-2 cells even at the highest selection dose). Elevated ABCB1 transcript expression was first detected at selection dose-9 and progressively increased to selection dose-12 13 .…”

Lipid Peroxidation in Colorectal Carcinogenesis: Bad and Good News

“…AKR1B10 is also up-regulated in many types of solid tumors (Fukumoto et al, 2005;Yoshitake et al, 2007;Breton et al, 2008;Satow et al, 2010), and its gene silencing results in growth inhibition of colorectal cancer cells (Yan et al, 2007), as well as in increasing HNE-elicited cell death (Matsunaga et al, 2011). Recently, some family members of AKR enzymes have been shown to be overexpressed and linked to resistance against anticancer drugs such as anthracyclines, cisplatin, and methotrexate (Veitch et al, 2009;Cheng al., 2008;Selga et al, 2008). As regarding colon cancer, experimental data suggest that the up-regulation of AKR1B10 was related with acquisition of resistance to the anticancer drug mitomycin-c (MMC) in HT-29 colon cancer cells (Matsunaga et al, 2011).…”