Epalrestat, an AKR1B1 inhibitor for diabetic patients, inhibits progression of BLBC
Basal-like breast cancer (BLBC) is an aggressive form of breast cancer with early recurrence, distant metastasis, and shorter survival rate that usually occurs in younger and premenopausal women. It can metastasize to the sites associated with a poor prognosis, such as the brain and the lungs. Recent research conducted in China had discovered a metabolic enzyme, aldo-keto reductase 1 member B1 (AKR1B1) that drives an aggressive type of breast cancer. The overexpression of AKR1B1 associates with BLBC and its expression promotes tumorigenicity and metastasis. An AKR1B1 inhibitor, Epalrestat, was approved to treat diabetic complications, but it has significantly suppressed cancer stem cell (CSC) properties, tumorigenicity, and metastasis of BLBC cells.
BLBC is found in around 15% to 20% of breast cancer patients where it spreads quick enough to induce early recurrence after treatment and increase frequency of progression to the brain and the lungs. Unfortunately, there are no effective therapies to target this form of aggressive and fatal breast cancer. BLBC possesses the activated epithelial-mesenchymal transition (EMT) program for tumor progression and metastasis. The EMT process allows resistance to treatment and initiation of tumor growth in other tissues. Also, EMT’s causal relationship with metabolic alteration would support the development of novel interventions for targeting metastatic breast cancer.
According to Prof. Chenfang Dong at the Zhejiang University School of Medicine in Hangzhou, China, it is noteworthy that epalrestat is already on the market without any major toxicity. Most significantly, a clinically achievable dose of epalrestat exhibits apparent inhibitory effect on BLBC using cellular and mice models. Moreover, this drug is used in Japan to treat peripheral neuropathies associated with diabetes. Since, it is on the market with no major adverse effects, it has the potential to become a valuable targeted drug in the clinical treatment of basal-like breast cancer.
This study provides a detailed understanding of the function and underlying mechanism of AKR1B1 associated with aggressiveness cancer. They discovered that AKR1B1 expression was induced by Twist2, a transcription factor known to play a central role in EMT. However, AKR1B1 elevated levels of Twist2 by producing prostaglandin F2, a lipid that activates the NF-B signaling pathway. An important “feedback loop” for basal-like cancer cells for EMT, thus reducing AKR1B1 levels that impaired the cells power to migrate and enhance to cancer stem cells. AKR1B1 inhibition, in turn, hindered the growth and metastasis of tumors formed by human basal-like breast cancer cells injected into mice as the data suggested that AKR1B1 overexpression represented an oncogenic episode causing the aggressive behaviors of BLBC.
AKR1B1 overexpression highly correlated with BLBC. Datasets were compared and analyzed by one-way ANOVA and two-tailed student’s T test. AKR1B1 and AKR1B1 mRNA expression was analyzed by western blotting and semiquantitative RT-PCR or real time PCR, respectively. Also, AKR1B1 positively correlated with Twist2 expression and was a direct transcriptional target of Twist2. Using Pearson’s correlation method and Spearman’s rank correlation test, the relative level of AKR1B1 plotted against Twist2 to analyze the correlation of public datasets. Also, AKR1B1 altered the expression of EMT markers and enhanced breast cancer cell migration and invasion. Moreover, AKR1B1 controlled intracellular PGF2α levels, mediated the NF-κB pathway and contributed to the maintenance of CSCs and was required for tumorigenicity and metastasis of breast cancer.
In conclusion, AKR1B1 overexpression correlated with BLBC and predicted the poor diagnosis in breast cancer patients. Mechanistically, Twist2 transcriptionally induces AKR1B1 expression, leading to nuclear factor κB (NF-κB) activation, which then up-regulates Twist2 expression, thus resulting in a positive feedback loop that is followed by the EMT program and enhances CSC–like properties in BLBC. AKR1B1 expression promotes tumorigenicity and metastasis, however AKR1B1 knockdown inhibits tumorigenicity and metastasis. The study identified AKR1B1 as a key modulator of tumor aggressiveness and suggested that its pharmacologic inhibition has the potential to become a valuable therapeutic strategy for BLBC.
- AKR1B1 expression promotes tumorigenicity and metastasis
- AKR1B1 knockdown inhibits tumorigenicity and metastasis.
- Epalrestat, an AKR1B1 inhibitor approved for the treatment of diabetic complications, significantly suppresses CSC properties, tumorigenicity, and metastasis of BLBC cells.
- Wu X, Li X, Fu Q, Cao Q, Chen X, Wang M, et al. AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program. J. Exp. Med. 2017, March 7.
- Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, et al. Basal-like and Triple-negative Breast Cancers: A Critical Review With an Emphasis on The Implications for Pathologists and Oncologists. Mod Pathol. 2011;24(2):157-167.
Tenzing Dolkar, BSc., PharmD Candidate 2017, Lake Erie College of Osteopathic Medicine, School of Pharmacy