Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues.
The antitumor sesquiterpene lactone helenalin, which is found in species of the plant genus Helenium, caused a marked potentiation of the increases in intracellular free Ca2+ concentration ([Ca2+]i) produced by mitogens such as vasopressin, bradykinin, and platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partly attenuated the increased [Ca2+]i responses caused by helenalin. The increased [Ca2+]i responses occurred at concentrations of helenalin that inhibited cell proliferation. At higher concentrations, helenalin inhibited the [Ca2+]i responses. No change in resting [Ca2+]i was caused by helenalin even at high concentrations. Other helenalin analogues also increased the [Ca2+]i response. Helenalin did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the effects of helenalin on [Ca2+]i responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells indicated that helenalin caused an increased accumulation of Ca2+ into nonmitochondrial 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 these stores.
Powis
G
G
Arizona Cancer Center, University of Arizona, Tucson 85724.
Gallegos
A
A
Abraham
R T
RT
Ashendel
C L
CL
Zalkow
L H
LH
Grindey
G B
GB
Bonjouklian
R
R
D016475:3T3 Cells; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D051379:Mice; D011493:Protein Kinase C / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction / Q000187:drug effects*
D000972:Antineoplastic Agents, Phytogenic; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C001329:helenalin; D011493:Protein Kinase C; D002118:Calcium