Tipifarnib-Induced Apoptosis in Acute Myeloid Leukemia and Multiple Myeloma Cells Depends on Ca²⁺Influx through Plasma Membrane Ca²⁺Channels

Abstract

A major contributing factor to the high mortality rate associated with acute myeloid leukemia and multiple myeloma is the development of resistance to chemotherapy. We have shown that the combination of tipifarnib, a nonpeptidomimetic farnesyltransferase inhibitor (FTI), with bortezomib, a proteosome inhibitor, promotes synergistic death and overcomes de novo drug resistance in acute myeloid leukemia cell lines. Experiments were undertaken to identify the molecular mechanisms by which tipifarnib produces cell death in acute myeloid leukemia and multiple myeloma cell lines (U937 and 8226, respectively). ] i overload. Preventing Ca 2ϩ influx diminished tipifarnib-evoked cell death, whereas 2-APB potentiated this effect, demonstrating a link between tipifarnib-induced Ca 2ϩ influx and apoptosis. These data suggest that tipifarnib exerts its effects by acting on a membrane channel with pharmacological properties consistent with store-operated channels containing the Orai3 subunit. It is noteworthy that Orai3 transcripts were found to be expressed at lower levels in tipifarnib-resistant 8226/R5 cells. Our results indicate tipifarnib causes cell death via a novel mechanism involving activation of a plasma membrane Ca 2ϩ channel and intracellular Ca 2ϩ overload.

Glucopsychosine increases cytosolic calcium to induce calpain-mediated apoptosis of acute myeloid leukemia cells

“…The increase in cytosolic calcium occurred 4-8 h following glucopsychosine treatment, which is consistent with other studies reporting slower increases in cytosolic calcium when the calcium originates from the extracellular space [79,80]. Increased cytosolic calcium resulted in calpain activation.…”

STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis

“…The authors reported higher Orai3 expression in Tipifarnib-sensitive myeloid leukemia cells in comparison to Tipifarnib-insensitive leukemia cells. Further, using pharmacological tools, Yanamandra et al (113) showed that Orai3 contributes to Tipifarnib-induced apoptosis in myeloid leukemia cell lines. In contrast to a large number of studies, Peng et al (81) reported that increased STIM1 expression and SOCE negatively regulate benign cancerous conditions of tuberous sclerosis complex.…”

Emerging roles of Orai3 in pathophysiology

“…They examined Orai3 mRNA levels in these cell lines and reported that tipifarnib-sensitive cells express higher levels of Orai3 mRNA compared with tipifarnib-resistant cells, suggesting that the difference in mRNA expression might explain Orai3 involvement in these cells. 74 Although the study by Yanamandra et al reported some interesting observations, …”

“…This group reported that some leukemic cell lines possess a tipifarnibactivated Ca 2+ influx pathway with a pharmacological profile similar to that of SOCE mediated by Orai3 in ER + breast cancer cells; tipifarnib-induced Ca 2+ influx is potentiated by 2-APB and blocked by lanthanides. 74 These authors correlated the extent of Ca 2+ entry with cell death and found that application of tipifarnib alone resulted in apoptosis; co-application of 2-APB increased apoptosis whereas co-application of lanthanides decreased tipifarnib-induced apoptosis. They examined Orai3 mRNA levels in these cell lines and reported that tipifarnib-sensitive cells express higher levels of Orai3 mRNA compared with tipifarnib-resistant cells, suggesting that the difference in mRNA expression might explain Orai3 involvement in these cells.…”

“…74 Tipifarnib is a non-peptidomimetic farnesyltransferase inhibitor that inhibits Ras kinase and is used in clinical trial for treatment of certain types of leukemia and breast cancers. This group reported that some leukemic cell lines possess a tipifarnibactivated Ca 2+ influx pathway with a pharmacological profile similar to that of SOCE mediated by Orai3 in ER + breast cancer cells; tipifarnib-induced Ca 2+ influx is potentiated by 2-APB and blocked by lanthanides.…”