OBJECTIVES: Recent studies suggest that tumor cells overexpressing aldoketoreductases (AKRs) exhibit increased resistance to DNA damaging agents such as anthracyclines. AKRs may induce resistance to the anthracycline doxorubicin by catalyzing its conversion to the less toxic 13-hydroxy metabolite doxorubicinol. However, it has not been established whether during selection for anthracycline resistance, AKR overexpression in tumor cells can be correlated with the onset or magnitude of drug resistance and with appreciable conversion of anthracyclines to 13-hydroxy metabolites. METHODS AND FINDINGS: Through microarray and quantitative polymerase chain reaction studies involving rigid selection criteria and both correlative discriminate statistics and time-course models, we have identified several genes whose expression can be correlated with the onset and/or magnitude of anthracycline resistance, including AKR1C2 and AKR1C3. Also associated with the onset or magnitude of anthracycline resistance were genes involved in drug transport (ABCB1, ABCC1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), protection from reactive oxygen species (AKR1C2, AKR1C3, FTL, FTH, TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). As expected, doxorubicin-resistant and epirubicin-resistant cells exhibited higher levels of doxorubicinol than wild-type cells, although at insufficient levels to account for significant drug resistance. Nevertheless, an inhibitor of Akr1c2 (5beta-cholanic acid) almost completely restored sensitivity to doxorubicin in ABCB1-deficient doxorubicin-resistant cells, while having no effect on ABCB1-expressing epirubicin-resistant cells. CONCLUSION: 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.
OBJECTIVES: Recent studies suggest that tumor cells overexpressing aldoketoreductases (AKRs) exhibit increased resistance to DNA damaging agents such as anthracyclines. AKRs may induce resistance to the anthracyclinedoxorubicin by catalyzing its conversion to the less toxic 13-hydroxy metabolite doxorubicinol. However, it has not been established whether during selection for anthracycline resistance, AKR overexpression in tumor cells can be correlated with the onset or magnitude of drug resistance and with appreciable conversion of anthracyclines to 13-hydroxy metabolites. METHODS AND FINDINGS: Through microarray and quantitative polymerase chain reaction studies involving rigid selection criteria and both correlative discriminate statistics and time-course models, we have identified several genes whose expression can be correlated with the onset and/or magnitude of anthracycline resistance, including AKR1C2 and AKR1C3. Also associated with the onset or magnitude of anthracycline resistance were genes involved in drug transport (ABCB1, ABCC1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), protection from reactive oxygen species (AKR1C2, AKR1C3, FTL, FTH, TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). As expected, doxorubicin-resistant and epirubicin-resistant cells exhibited higher levels of doxorubicinol than wild-type cells, although at insufficient levels to account for significant drug resistance. Nevertheless, an inhibitor of Akr1c2 (5beta-cholanic acid) almost completely restored sensitivity to doxorubicin in ABCB1-deficient doxorubicin-resistant cells, while having no effect on ABCB1-expressing epirubicin-resistant cells. CONCLUSION: 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.
Authors: K N Kashkin; E A Musatkina; A V Komelkov; I A Favorskaya; E V Trushkin; V A Shleptsova; D A Sakharov; T V Vinogradova; E P Kopantzev; M V Zinovyeva; O V Kovaleva; I B Zborovskaya; A G Tonevitsky; E D Sverdlov Journal: Dokl Biochem Biophys Date: 2010 Jan-Feb Impact factor: 0.788
Authors: Niels F Jensen; Jan Stenvang; Mette K Beck; Barbora Hanáková; Kirstine C Belling; Khoa N Do; Birgitte Viuff; Sune B Nygård; Ramneek Gupta; Mads H Rasmussen; Line S Tarpgaard; Tine P Hansen; Eva Budinská; Per Pfeiffer; Fred Bosman; Sabine Tejpar; Arnaud Roth; Mauro Delorenzi; Claus L Andersen; Maria U Rømer; Nils Brünner; José M A Moreira Journal: Mol Oncol Date: 2015-02-24 Impact factor: 6.603
Authors: Pei Jye Voon; Hui Ling Yap; Cho-Yee-Thu Ma; Fan Lu; Andrea L A Wong; Nur Sabrina Sapari; Richie Soong; Thomas I P Soh; Boon-Cher Goh; How-Sung Lee; Soo-Chin Lee Journal: Br J Clin Pharmacol Date: 2013-06 Impact factor: 4.335
Authors: Viktor Hlaváč; Veronika Brynychová; Radka Václavíková; Marie Ehrlichová; David Vrána; Václav Pecha; Markéta Trnková; Roman Kodet; Marcela Mrhalová; Kateřina Kubáčková; Jiří Gatěk; Petr Vážan; Pavel Souček Journal: Medicine (Baltimore) Date: 2014-12 Impact factor: 1.889
Authors: Stephen R Armstrong; Rashmi Narendrula; Baoqing Guo; Amadeo M Parissenti; Katherine L McCallum; Stephanie Cull; Carita Lannér Journal: J Ovarian Res Date: 2012-11-30 Impact factor: 4.234