Effects and mechanisms of AKR1C3 inducing doxorubicin resistance in breast cancer / 中国药科大学学报

@#To explore the mechanisms by which AKR1C3 induces tumor resistance, human breast cancer cell strain MCF-7/DOX resistant to doxorubicin, MCF-7/ AKR1C3 cells for overexpression of AKR1C3 and MCF-7/DOX-KD cells for knockdown of AKR1C3 in MCF-7/DOX cells were established. Western blot analysis found that AKR1C3 was expressed at a higher level in MCF-7/DOX than MCF-7 wild type cells. Similarly, CCK-8 and DAPI confirmed that MCF-7/ AKR1C3 cells were more resistant to DOX than AKR1C3 wild types as the IC50 was increased 6 times in MCF-7/AKR1C3 cells more than in AKR1C3 wild type cells. Meanwhile, colony formation ability was also enhanced after AKR1C3 was over-expressed in MCF-7 cells.Cytoplasmic/nuclear separation analysis and IF further found that β-catenin nuclear translocation mediated by AKR1C3 was the main reason contributing to the occurrence of DOX-resistant breast cancer cells. β-catenin inhibitor, XAV939, could reverse the AKR1C3 induced doxorubicin resistance in MCF-7 cells.Results indicated that AKR1C3 could be a potential therapeutic target in breast cancer cells.

AKR1B10 inhibitor enhances the inhibitory effect of sorafenib on liver cancer xenograft / 中华肝脏病杂志

Objective@#To investigate the inhibitory effect of AKR1B10 inhibitor combined with sorafenib on hepatocellular carcinoma (HCC) xenograft growth.@*Methods@#HepG2 xenograft model was established in nude mice. The mice were then randomly divided into four groups: control group, epalrestat monotherapy group, sorafenib monotherapy group and combination treatment group. Tumor volume, tumor weight, T/C ratio and the change in body weight of nude mice in each group were compared to evaluate the curative effect. Immunohistochemistry staining was used to detect the expression of Ki-67 in tumor tissues to evaluate the proliferation status of tumor cells. One-way analysis of variance was used to compare the differences between the groups. Student’s t-test was used to test means of two groups and chi-square test was used for multiple samples.@*Results@#The differences of the grafted tumor volume before and after treatment between the control group, epalrestat group, sorafenib group and combined therapy group was 238.940 ± 39.813, 124.991 ± 84.670, -26.111 ± 11.518, and -54.072 ± 17.673(mm3), respectively, (F = 37.048, P < 0.001). The tumor mass were 0.273 ± 0.140, 0.158 ± 0.078, 0.079 ± 0.054, 0.045 ± 0.024 (g), (F = 16.594, P < 0.001); T/C ratio were 100%, 57.9%, 28.9%, 16.5%, and Ki-67 positive rate were 23.295 ± 6.218, 13.503 ± 3.392, 7.325 ± 2.257, 4.664 ± 1.189 (%), (χ2 = 822.203, P < 0.001) . The tumor volume (t = -3.579, P = 0.002) and Ki-67 positive rate (t = -10.003, P < 0.001) in epalrestat monotherapy group were significantly lower than control group. The tumor volume (t = 2.056, P = 0.025), tumor mass (t = 2.101, P = 0.043), and Ki-67 positive rate (t = -2.850, P = 0.005) in combination treatment group were significantly lower than sorafenib monotherapy group. Compared with the control group, the body weight of nude mice in the treatment group decreased to a certain extent, but there was no statistically significant difference between epalrestat monotherapy group and control group (t = -1.599, P = 0.262), and combined therapy and sorafenib monotherapy group (t = -0.051, P = 0.96).@*Conclusion@#AKR1B10 inhibitor enhanced the inhibitory effect of sorafenib on hepatocellular carcinoma xenograft.

Berberine inhibits androgen synthesis by interaction with aldo-keto reductase 1C3 in 22Rv1 prostate cancer cells / 亚洲男科学杂志(英文版)

Aldo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aldo-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rv1 cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family 1 member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form p-p interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family 1 member C3 enzyme activity and the inhibition of 22Rv1 prostate cancer cell growth by decreasing the intracellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKR1C3 inhibitors using berberine as the lead compound.

Aldo-keto reductase superfamily and lung cancer / 国际肿瘤学杂志

Aldo-keto reductase reductase (AKR) superfamily is NADPH-dependent oxidoreductase.As a rate-limiting enzyme in polyols metabolic pathway,the activation or inactivation of AKR involves in neoplastic process of lung cancer with the metabolism of environment toxic.AKR is related to drug resistance of chemotherapy,which will be the prognostic factor of lung cancer.

Application of AKRIB10 combined with GPC-3 in immunohistochemical diagnosis of hepatocellular carcinoma / 第二军医大学学报

Objective To explore the value of AKRIBIO combined with GPC-3 in improving the sensitivity and specificity of immunohistochemical diagnosis of hepatocellular carcinoma (HCC). Methods The microarray including 75 HCC and adjacent tissues was subjected to immunohistochemistry detection of AKRIBIO and GPC-3 expression. A Logistic regression diagnostic model was established using the results of tissue microarray (training group). The ROC curves (the receiver-operating characteristic curve) and area under the curve (AUC) were used to evaluate the sensitivity and specificity of AKRIBIO, GPC-3 or their combination. The Logistic regression diagnostic model was validated with 200 HCC and adjacent tissues (testing group). Results For the training group, the AUC values of AKRIBIO, GPC-3, and AKRIBIO combined with GPC-3 were 0. 773, 0. 800, and 0. 931, respectively. The sensitivity of AKRIBIO and GPC-3 were 56% and 61. 3%, respectively, and their specificity was both 98. 7%. AKRIBIO combined with GPC-3 yielded a sensitivity of 88. 0% and a specificity of 97. 3%. For the testing group, sensitivity and specificity of AKRIBIO combined with GPC-3 were 97. 0% and 96. 5%, respectively. Conclusion AKRIBIO combined with GPC-3 can greatly improve the sensitivity and specificity of HCC immunohistochemical diagnosis, and it should be used when necessary in addition to the routine pathological assessment.