Malignant mesothelioma (MM) is a currently incurable, aggressive
cancer derived from mesothelial cells, most often resulting from
asbestos exposure. The current first-line treatment in unresectable MM is
cisplatin/
pemetrexed, which shows very little long-term effectiveness, necessitating research for novel therapeutic interventions. The existing
chemotherapies often act on the cytoskeleton, including actin filaments and microtubules, but recent advances indicate the 'fourth' form consisting of the family of
septins, representing a novel target. The
septin inhibitor
forchlorfenuron (FCF) and FCF analogs inhibit MM cell growth in vitro, but at concentrations which are too high for clinical applications. Based on the reported requirement of the
chloride group in the 2-position of the
pyridine ring of FCF for MM cell growth inhibition and cytotoxicity, we systematically investigated the importance (cell growth-inhibiting capacity) of the
halogen atoms
fluorine,
chlorine,
bromine and
iodine in the 2- or 3-position of the
pyridine ring. The MM cell lines ZL55, MSTO-211H, and SPC212, and-as a control-immortalized Met-5A mesothelial cells were used. The potency of the various
halogen substitutions in FCF was mostly correlated with the atom size (covalent radius); the small
fluoride analogs showed the least effect, while the largest one (
iodide) most strongly decreased the MTT signals, in particular in MM cells derived from epithelioid MM. In the latter, the strongest effects in vitro were exerted by the 2-iodo and, unexpectedly, the 2-trifluoromethyl (2-CF3) FCF analogs, which were further tested in vivo in mice. However, FCF-2-I and, more strongly, FCF-2-CF3 caused rapidly occurring strong symptoms of systemic toxicity at doses lower than those previously obtained with FCF. Thus, we investigated the effectiveness of FCF (and selected analogs) in vitro in MM cells which were first exposed to
cisplatin. The slowly appearing population of
cisplatin-resistant cells was still susceptible to the growth-inhibiting/cytotoxic effect of FCF and its analogs, indicating that
cisplatin and FCF target non-converging pathways in MM cells. Thus, a combination
therapy of
cisplatin and FCF (analogs) might represent a new avenue for the treatment of repopulating chemo-resistant MM cells in this currently untreatable
cancer.