Minerval induces apoptosis in Jurkat and other cancer cells

Abstract

Minerval is an oleic acid synthetic analogue that impairs lung cancer (A549) cell proliferation upon modulation of the plasma membrane lipid structure and subsequent regulation of protein kinase C localization and activity. However, this mechanism does not fully explain the regression of tumours induced by this drug in animal models of cancer. Here we show that Minerval also induced apoptosis in Jurkat T-lymphoblastic leukaemia and other cancer cells. Minerval inhibited proliferation of Jurkat cells, concomitant with a decrease of cyclin D3 and cdk2 (cyclin-dependent kinase2). In addition, the changes that induced on Jurkat cell membrane organization caused clustering (capping) of the death receptor Fas (CD95), caspase-8 activation and initiation of the extrinsic apoptosis pathway, which finally resulted in programmed cell death. The present results suggest that the intrinsic pathway (associated with caspase-9 function) was activated downstream by caspase-8. In a xenograft model of human leukaemia, Minerval also inhibited tumour progression and induced tumour cell death. Studies carried out in a wide variety of cancer cell types demonstrated that apoptosis was the main molecular mechanism triggered by Minerval. This is the first report on the pro-apoptotic activity of Minerval, and in part explains the effectiveness of this non-toxic anticancer drug and its wide spectrum against different types of cancer.

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

“…Folinic acid also impaired the apoptosis induced by HOA in Jurkat cells (2), as witnessed by a decrease in the subG 1 peak ( These results clearly indicate the specificity of HOA and the relevance of DHFR in inducing cell cycle arrest in A549 cells and apoptosis in Jurkat cells. However, the fact that this recovery was not complete in both cell lines suggests that other pathways are also likely to be regulated by this drug.…”

“…This second signal or pathway would define the final and complete anticancer effect of the drug (either inhibition of cell growth or apoptosis), and it might originate from the plasma membrane, from a downstream molecular event leading to DHFR reduction or from both. An example of such simultaneous membrane signals might be the induction of Fas receptor clustering in Jurkat cells (2). By contrast, the divergent effect of impairing cyclin and cdk activity that leads to cell cycle arrest in A549 or apoptosis in Jurkat cells, may also reflect the downstream crosstalk mechanisms (2,3,(21)(22)(23).…”

“…An example of such simultaneous membrane signals might be the induction of Fas receptor clustering in Jurkat cells (2). By contrast, the divergent effect of impairing cyclin and cdk activity that leads to cell cycle arrest in A549 or apoptosis in Jurkat cells, may also reflect the downstream crosstalk mechanisms (2,3,(21)(22)(23).…”

“…Although HOA induces cell cycle exit in human lung cancer (A549) cells (1), it induces apoptosis in human leukemia cells (2). The IC 50 of this drug for most cancer cells studied is in the range of M, whereas its IC 50 in normal cells is over 5,000 M (2).…”

“…The IC 50 of this drug for most cancer cells studied is in the range of M, whereas its IC 50 in normal cells is over 5,000 M (2). Thus, this drug does not produce toxicity at therapeutic doses despite acting efficiently in cell and animal models of human cancers (2,3). Hence, it is important to define the mode of action of this compound and whether common molecular events underlie its therapeutic effects and the regression of different types of cancer.…”