PLoS One. 2013 Jun 10;8(6):e65113.

Deguelin action involves c-Met and EGFR signaling pathways in triple negative breast cancer cells.

Mehta R, Katta H, Alimirah F, Patel R, Murillo G, Peng X, Muzzio M, Mehta RG.

Cancer Biology and Analytical Chemistry Divisions, IIT Research Institute, Chicago, Illinois, United States of America. RMehta@iitri.org

 

ABSTRACT

BACKGROUND: Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC) has become a major focus of investigations for many laboratories. Recently, Deguelin, a natural product isolated from African plant Mundulea sericea (Leguminossae) has shown both antiproliferative actions in various cancers including breast as well as chemoprenventive activity against carcinogen induced experimental cancers. In this report we evaluated efficacy and mechanism of action of Deguelin in triple negative breast cancer cell lines.

METHODS/FINDINGS: In vitro, Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells. Deguelin (2 or 4 mg/kg body weight), when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study. The western blot analyses and immunostaining studies indicated that the deguelin effects may be mediated through EGFR-PAKT/c-Met p-ERK and NF-κB by down regulating their downstream targets such as p-STAT3, c-Myc, Survivin.

CONCLUSION/SIGNIFICANCE: These results suggest that Deguelin may have a significant therapeutic value for the treatment of TNBC patients.

PMID: 23762292

 

Supplementary Information:

The major concern in developing Deguelin as a possible therapeutic agent has been its reported neurotoxicity. It has been reported that Deguelin given continuously by infusion caused Parkinson’s-like symptoms in mice, however many reports in the last few years have indicated that Deguelin given orally or via i.p for a long period of time (for example orally for 90 days in mammary carcinogenesis studies), is well tolerated without causing any serious side effects including Parkinson’s like symptoms. In this study animals receiving Deguelin 4mg/kg body weight for 20 days showed no signs of toxicity as evident from body weight and other organ weights comparison with those in the control group.

Based on the results in the present study we believe that Deguelin inhibits cell growth in the triple negative breast cancer (TNBC) cells. In selective cell lines Deguelin affects EGFR and c-Met expression, which leads to down regulation of p-AKT, p-ERK, NFB and phosphor-STAT 3, which thereby reduces expression of their downstream targets such as c-Myc and Survivin as shown in Figure 1. Importantly, these results indicate that Deguelin is effective in suppressing growth of MDA-MB-231 cells both in vitro and in vivo. These cells are highly aggressive and harbor K-ras mutation. This finding has a major impact and strongly suggests that Deguelin at non-toxic concentration could be of great therapeutic value not only in TNBC but also other tumor types that are known to harbor K-ras mutation. Thus, further clinical evaluation of Deguelin either as a single therapeutic agent or in combination with known therapeutic agents for TNBC patients is warranted.

Rajendra Mehta-fig1Figure 1. Schematic diagram showing mechanism of Deguelin action in triple negative breast cancer cells. Deguelin affects EGFR/c-Met and their downstream target molecules such as p-STAT3, p-ERK, p-AKT, c-Myc and Survivin and there by affect growth/survival of breast cancer cells. Three different pathways affected by Deguelin are shown by different colors;, STAT3 (green), AKT (blue), ERK (red). Blue arrows with red outline shows molecules shown to be affected by Deguelin in this study. Red dotted line indicates possible alternative IL-6 mediated pathway, which is not explored in this study.

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