INCREASED INTRACELLULAR CA2+ SIGNALING CAUSED BY THE ANTITUMOR AGENT HELENALIN AND ITS ANALOGS

The antitumor sesquiterpene lactone helenalin, which is found in speci es of the plant genus Helenium, caused a marked potentiation of the in creases in intracellular free Ca2+ concentration ([Ca2+](i)) produced by mitogens such as vasopressin, bradykinin, and platelet-derived grow th factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partl y attenuated the increased [Ca2+](i) responses caused by helenalin. Th e increased [Ca2+](i) responses occurred at concentrations of helenali n that inhibited cell proliferation. At higher concentrations, helenal in inhibited the [Ca2+](i) responses. No change in resting [Ca2+](i) w as caused by helenalin even at high con centrations. Other helenalin a nalogues also increased the [Ca2+](i) response. Helenalin did not inhi bit protein kinase C (PKC) and PKC appeared to play a minor role in th e effects of helenalin on [Ca2+](i) responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells ind icated that helenalin caused an increased accumulation of Ca2+ into no nmitochondrial stores and that the potentiating effect of helenalin on mitogen-stimulated [Ca2+](i) responses was due in part to an increase in the inositol-(1,4,5)-trisphosphate-mediated release of Ca2+ from t hese stores.