Development of Potent Forchlorfenuron Analogs and Their Cytotoxic Effect in Cancer Cell Lines

Kyu Kwang Kim,Aaron Jones,Richard G Moore,Rakesh K Singh,Niloy A Singh,Arif Kodza,Umayal Sivagnanalingam,Rachael Turner,Negar Khazan,Mary Towner,Hiroaki Itamochi

doi:10.1038/s41598-020-59824-4

Kyu Kwang Kim, Aaron Jones + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-59824-4

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Abstract

Forchlorfenuron (FCF) is a synthetic plant cytokinin widely used in agriculture to promote fruit size, that paradoxically inhibits proliferation, migration, and invasion in human cancer cell lines. FCF has also been shown to affect HIF-1α and HER2, which are both known to play a crucial role in cancer cell survival. In this study, we have developed potent FCF analogs through structural modification of FCF, coined UR214-1, UR214-7, and UR214-9. Compared to parental FCF, these analogs are more effective in decreasing viability and proliferation in both ovarian and endometrial cancer cell lines. These FCF analogs also suppress HER2 expression at a concentration lower than that of FCF. In addition, we found that treatment with either FCF or its analogs decreases the expression of human epididymis protein 4 (HE4), which is commonly upregulated in ovarian and endometrial cancers. Given the association between cancer behavior and HE4 production in gynecologic cancers, our findings may provide insight useful in the development of new treatment strategies for gynecologic cancers.

Highlights

Malignancy of the ovary and uterus is relatively common and quite lethal
We explored whether FCF or FCF analogs contribute to human epididymis protein 4 (HE4) secretion, which has been linked to the progression of ovarian cancer as well as poor patient outcomes, including advanced disease and decreased survival[8]
We found that treatment with FCF reduced cell viability in ovarian and endometrial cancer cell lines in the range 100–300 μM, which is pharmacologically undesirable

Summary

Introduction

Malignancy of the ovary and uterus is relatively common and quite lethal. Ovarian cancer is more fatal yet, with a 5-year survival of 46.6% (www.cdc.gov/cancer/dataviz, June 2019) Current treatment of these diseases relies on a combination of surgical and medical management. We have conducted a focused, structure-activity relationship study to optimize the chemical structure of FCF, with the goal of developing potent FCF analogs that could be tested for cytotoxic activity against a panel of gynecologic cancer cell lines. We hope such a compound could potentially be utilized as a future research tool. We delve into the role of FCF analogs on cancer cell growth factor receptor expression

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