Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells

Tak, Eunyoung; Lee, Seonmin; Lee, Jisun; Rashid, M. A.; Kim, Youn Wha; Park, Jae Hoon; Park, Won Sang; Shokat, Kevan M.; Ha, Joohun; Kim, Sung Soo

doi:10.1016/j.jhep.2010.06.045

Cited by 69 publications

(51 citation statements)

References 33 publications

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“…Further study from transfected cells has indicated that inhibition of HIF-1α expression lead to an increase in apoptosis of laryngeal cancer cells under hypoxic conditions. Almost consistent with the results of Liu et al (2008) and Tak et al (2011), our results elucidated that HIF-1α might partly be involved in hypoxia-induced MDR in laryngeal cancer cells via suppressing drug-induced apoptosis. The underlying mechanisms of HIF-1α in suppression of apoptosis in laryngeal cancer cells induced by chemotherapeutic drugs remains to be further determined.…”

Section: Discussionsupporting

confidence: 90%

Hypoxia Induced Multidrug Resistance of Laryngeal Cancer Cells via Hypoxia-inducible Factor-1α

Li¹,

Dong²,

Wang³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Section: Discussionsupporting

confidence: 90%

Hypoxia Induced Multidrug Resistance of Laryngeal Cancer Cells via Hypoxia-inducible Factor-1α

Li¹,

Dong²,

Wang³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…Although the proteasome pathway rapidly degrades HIF-1a under normoxia, this protein is stable under hypoxia, where it translocates to the nucleus and binds to hypoxia response elements (HREs) within the promoter of its target genes. Significant evidence indicates that HIF-1a plays an important role in the resistance to chemotherapy of hepatocellular carcinoma (12,13). Hence, inhibition of the HIF-1a pathway is a promising approach for the treatment of hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

Cai

Liu

Zhu

et al. 2014

Molecular Cancer Therapeutics

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Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1a (HIF-1a) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1a expression by decreasing HIF-1a protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1a protein, decreased the HIF-1a transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1a is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1a is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers. Mol Cancer Ther; 13(3); 630-42. Ó2013 AACR.

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“…ONE was purchased from Cayman Chemical (Ann Arbor, MI, U.S.A.); quercetin (QUE) was from Sigma-Aldrich (St. Louis, MO, U.S.A.); sulforaphane (SFN) was from LKT Laboratories (St. Paul, MN, U.S.A.); and Taq DNA polymerase was from TaKaRa (Kusatsu, Japan). TRIzol reagent, Superscript III reverse transcriptase, oligo(dT) [12][13][14][15][16][17][18] primer and Lipofectamine 2000 were obtained from Invitrogen (Carlsbad, CA, U.S.A.). All other chemicals were of the highest grade that could be obtained commercially.…”

Section: Methodsmentioning

confidence: 99%

“…PCR Analyses Total RNA was isolated from treated cells using the TRIzol reagent, and single-stranded cDNA was prepared from the total RNA sample by incubation for 50 min at 42°C with Superscript III reverse transcriptase and oligo-(dT) [12][13][14][15][16][17][18] primer. The cDNA for CBR1 was amplified from the single-stranded cDNA sample (5 µg) by semiquantitative PCR using the specific primers as reported previously.…”

Section: Methodsmentioning

confidence: 99%

“…9,16) To our knowledge, there are only three reports that propose the contribution of CBR1 to the mechanism underlying DOX resistance of breast cancer cells and hepatocellular carcinomas. [17][18][19] In this study, we monitored the expression of CBR1 in seven gastrointestinal cells, of which MKN45, LoVo and DLD1 cells with intrinsically different levels of CBR1 expression were chosen in order to establish the DOX-resistant variants. Since reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses revealed the up-regulation of CBR1 in the established DOX-resistant phenotypes of MKN45 and LoVo cells, the pathophysiological role of the enzyme in the DOX resistance was investigated by analyzing effects of its transient overexpression and specific inhibition on cytotoxicity of DOX.…”

Section: Up-regulation Of Carbonyl Reductase 1 Renders Development Ofmentioning

confidence: 99%

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Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

Matsunaga

Kezuka

Morikawa

et al. 2015

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX) is widely used for the treatment of a wide range of cancers such as breast and lung cancers, and malignant lymphomas, but is generally less efficacious in gastrointestinal cancers. The most accepted explanation for the DOX refractoriness is its resistance development. Here, we established DOX-resistant phenotypes of human gastric MKN45 and colon LoVo cells by continuous exposure to incremental concentrations of the drug. While the parental MKN45 and LoVo cells expressed carbonyl reductase 1 (CBR1) highly and moderately, respectively, the gain of DOX resistance further elevated the CBR1 expression. Additionally, the DOX-elicited cytotoxicity was lowered by overexpression of CBR1 and inversely strengthened by knockdown of the enzyme using small interfering RNA or pretreating with the specific inhibitor quercetin, which also reduced the DOX refractoriness of the two resistant cells. These suggest that CBR1 is a key enzyme responsible for the DOX resistance of gastrointestinal cancer cells and that its inhibitor is useful in the adjuvant therapy. Although CBR1 is known to metabolize DOX to a less toxic anticancer metabolite doxorubicinol, its overexpression in the parental cells hardly show significant reductase activity toward low concentration of DOX. In contrast, the overexpression of CBR1 increased the reductase activity toward an oxidative stress-derived cytotoxic aldehyde 4-oxo-2-nonenal. The sensitivity of the DOX-resistant cells to 4-oxo-2-nonenal was lower than that of the parental cells, and the resistance-elicited hyposensitivity was almost completely ameliorated by addition of the CBR1 inhibitor. Thus, CBR1 may promote development of DOX resistance through detoxification of cytotoxic aldehydes, rather than the drug's metabolism.Key words carbonyl reductase 1; doxorubicin; drug resistance; gastrointestinal cancer cell; quercetin An anthracycline-based antibiotic doxorubicin (DOX) is widely utilized for the treatment of patients not only with solid tumors formed in many organs including breast, lung and stomach, but also with malignant lymphomas. 1) One of the major anticancer actions of DOX is intercalation into the double-stranded DNA and the resultant inhibition of DNA/RNA polymerases.1) In addition, treatment with the drug is known to form the tripartite complex with DNA and topoisomerase-II, ultimately blocking the transcription and replication of DNA. Besides the events essential for protein biosynthesis and cell proliferation, the free radical formation is proposed as another cytolethal mechanism triggered by DOX.1-3) Cellular reductases such as cytochrome P450 reductase 4) and xanthine oxidase 5) catalyze the one-electron reduction of the p-quinone structure in the anthraquinone ring of DOX into a semiquinone radical intermediate, which in turn reacts with molecular oxygen to yield superoxide anion radical. The radical is further converted into a more potent oxidizing agent hydroxyl radical, and thereby oxidatively modifies intracellular components such as nucleic acids, lipids an...

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Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells

Cited by 69 publications

References 33 publications

Hypoxia Induced Multidrug Resistance of Laryngeal Cancer Cells via Hypoxia-inducible Factor-1α

Hypoxia Induced Multidrug Resistance of Laryngeal Cancer Cells via Hypoxia-inducible Factor-1α

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α

Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

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