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Published on: September 12, 2019
Fenretinide: a novel treatment for endometrial cancer
Navdha Mittal1, Saurabh Malpani1, Matthew Dyson1
1Division of Reproductive Biology, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States of America.
Abstract:
Resistance to progestin treatment is a major hurdle in the treatment of advanced and reoccurring endometrial cancer. Fenretinide is a synthetic retinoid that has been evaluated in clinical trials as a cancer therapeutic and chemo-preventive agent. Fenretinide has been established to be cytotoxic to many kinds of cancer cells. In the present study, we demonstrate that fenretinide decreased cell viability and induced apoptosis in Ishikawa cells, which are an endometrial cancer cell line, in dose dependent manner in-vitro. This effect was found to be independent of retinoic acid nuclear receptor signaling pathway. Further, we have shown that this induction of apoptosis by fenretinide may be caused by increased retinol uptake via STRA6. Silencing of STRA6 was shown to decrease apoptosis which was inhibited by knockdown of STRA6 expression in Ishikawa cells. Results of an in-vivo study demonstrated that intraperitoneal injections of fenretinide in endometrial cancer tumors (created using Ishikawa cells) in mice inhibited tumor growth effectively. Immunohistochemistry of mice tumors showed a decrease in Ki67 expression and an increase in cleaved caspase-3 staining after fenretinide treatment when compared to vehicle treated mice. Collectively, our results are the first to establish the efficacy of fenretinide as an antitumor agent for endometrial cancer both in-vitro and in-vivo, providing a valuable rationale for initiating more preclinical studies and clinical trials using fenretinide for the treatment of endometrial cancer.
Insights
Fenretinide effectively reduced endometrial cancer cell viability and tumor growth in preclinical models. This synthetic retinoid shows promise as a novel treatment for endometrial cancer, warranting further clinical investigation.
Area of Science:
- Oncology
- Pharmacology
Background:
- Progestin treatment resistance is a significant challenge in advanced and recurrent endometrial cancer.
- Fenretinide, a synthetic retinoid, exhibits cytotoxic effects against various cancer cells and has been explored as a therapeutic and chemopreventive agent.
Purpose of the Study:
- To investigate the efficacy of fenretinide as a treatment for endometrial cancer.
- To elucidate the mechanism of fenretinide-induced apoptosis in endometrial cancer cells.
Main Methods:
- In vitro studies using Ishikawa endometrial cancer cells to assess cell viability and apoptosis.
- In vivo studies involving xenograft mouse models of endometrial cancer treated with fenretinide.
- Analysis of apoptosis markers (cleaved caspase-3) and proliferation marker (Ki67) via immunohistochemistry.
Main Results:
- Fenretinide dose-dependently decreased cell viability and induced apoptosis in Ishikawa cells, independent of retinoic acid nuclear receptor signaling.
- Increased retinol uptake via STRA6 was identified as a potential mechanism for fenretinide-induced apoptosis, as STRA6 silencing reduced this effect.
- In vivo, fenretinide treatment significantly inhibited tumor growth in mice and decreased Ki67 while increasing cleaved caspase-3 expression in tumors.
Conclusions:
- Fenretinide demonstrates significant antitumor activity against endometrial cancer both in vitro and in vivo.
- The findings support fenretinide as a potential therapeutic agent for endometrial cancer, justifying further preclinical and clinical research.
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