The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo

Abstract

Malignant mesothelioma (MM) is one of the most aggressive cancer types with a patient’s life expectancy of typically less than one year upon diagnosis. The urgency of finding novel therapeutic approaches to treat mesothelioma is evident. Here we tested the effect of the plant-growth regulator forchlorfenuron (FCF), an inhibitor of septin function(s) in mammalian cells, on the viability and proliferation of MM cell lines, as well as other tumor cell lines derived from lung, prostate, colon, ovary, cervix and breast. Exposure to FCF strongly inhibited proliferation of human and mouse (most efficiently epithelioid) MM cells and all other tumor cells in a concentration-dependent manner and led to cell cycle arrest and cell death. The role of septin 7 (SEPT7), a presumably essential target of FCF in MM cells was confirmed by an shRNA strategy. FCF was robustly inhibiting tumor cell growth in vitro at low micromolar (IC50: ≈20-60µM) concentrations and more promisingly also in vivo. Initial experiments with FCF analogous revealed the importance of FCF’s chloride group for efficient cell growth inhibition. FCF’s rather low systemic toxicity might warrant for an extended search for other related and possibly more potent FCF analogues to target MM and putatively other septin-dependent tumors.

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

“…FCF shows potent cytokinin activity and has been used worldwide as a plant fertilizer that increases fruit size. Interestingly, FCF has been shown to inhibit proliferation, anchorage independent growth, migration and invasion of cancer cell lines [4][5][6] . The effect of FCF has been demonstrated in various cancer types, including prostate, mesothelioma, lung, colon, breast, ovary and cervix 4 .…”

“…Interestingly, FCF has been shown to inhibit proliferation, anchorage independent growth, migration and invasion of cancer cell lines [4][5][6] . The effect of FCF has been demonstrated in various cancer types, including prostate, mesothelioma, lung, colon, breast, ovary and cervix 4 . FCF was also found to be effective in a mouse model, in which tumor growth was inhibited 4 .…”

“…The effect of FCF has been demonstrated in various cancer types, including prostate, mesothelioma, lung, colon, breast, ovary and cervix 4 . FCF was also found to be effective in a mouse model, in which tumor growth was inhibited 4 . At a molecular level, FCF treatment causes the suppression of HIF-1α and HER2, both of which are known to be associated with more malignant cancer phenotypes 6,7 .…”

Aberrant Migratory Behavior of Immune Cells in Recurrent Autoimmune Uveitis in Horses

“…In mammalian cell lines, FCF treatment causes highly intertwined and more densely packed, abnormally large septin structures, leading to reduced transmigration ability through small pores in transmigration assays (Hu et al, 2008). In another model with malignant mesothelioma cells from man and mice, treatment of respective cells with FCF resulted in accumulation of septin 7 structures along the plasma membrane, affecting the organization dynamics of septin filaments (Blum et al, 2019). Although we could not detect such decreased migration ability in FCF-treated cells (Figure 5), FCF treatment of primary cells used in our study similarly increased septin 7 density at the cell membrane and additionally triggered a shift of septin 7 structures to perinuclear regions ( Figures 6I-L), which was even more prominent after cells had migrated (Figures 6M-P).…”

Novel Functions of the Septin Cytoskeleton

“…Furthermore, possible off-target effects and animal tissue toxicity of FCF have been reported. 28,111,113 Nevertheless, studies utilizing FCF have laid the ground for the development of next-generation septin inhibitors. We expect that these inhibitors will be first developed as anticancer drugs, given the substantial body of evidence about mutations or altered expression of different septin paralogs being associated with tumorigenesis.…”