Perillyl Alcohol Inhibits TCR-Mediated [Ca2+]i Signaling, Alters Cell Shape and Motility, and Induces Apoptosis in T Lymphocytes

Abstract

Perillyl alcohol (POH) inhibits isoprenylation and has shown anticancer and chemopreventive properties in rodent models. The mechanism that underlies the anticancer activity of POH and other isoprenylation inhibitors is unknown but has been postulated to involve decreased levels of isoprenylated Ras and Rasrelated proteins. Previously we demonstrated that POH effectively inhibits human T cell proliferation in vitro and can prevent acute and chronic rejection in a rat cardiac transplant model. In this report, we investigate the effects of POH on T lymphocytes at the single-cell level. POH disrupts the polarized shape and motility of antigen-specific murine 1E5 T cells. Using an optical trap to position anti-CD3-coated beads in contact with 1E5 T cells, we demonstrate that POH inhibits their TCR-mediated calcium response. Furthermore, we show that POH preferentially induces apoptosis in PHA-activated human T cells as well as in 1E5 T cells.

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

“…2B), suggesting that inhibition of farnesyltransferase alone is not sufficient to elicit the [Ca 2ϩ ] i overload. It is noteworthy that the FTI perillyl alcohol has also been shown to elevate Ca 2ϩ , induce membrane boiling, and promote apoptosis in activated T lymphocytes (Wei et al, 2000). The effects of perillyl alcohol on T lymphocyte, however, were biphasic and more rapid than those reported here for tipifarnib (Ͻ1 min).…”

Farnesyltransferase inhibition: a novel method of immunomodulation

“…We have shown previously that perillyl alcohol, a geranylgeranyltransferase inhibitor, caused 1E5 T cells to lose their polarized shape and that these round cells failed to activate when placed in contact with an anti-CD3 antibodycoated bead [36]. This loss of polarized shape induced by perillyl alcohol was identical to the effects of cytochalasin D, an anti-actin agent, and dissimilar to the effects of colchicine, an antimicrotubule agent.…”

Ten-Year Follow-Up of a Randomized Trial of Pravastatin in Heart Transplant Patients

“…Statins reduce cholesterol production and reduce isoprenylation of certain proteins, such ras and ras-related proteins, that appear to be important in T-cell activation and effector function and are pivotal in the development of allograft rejection during organ transplantation. [15][16][17] Pravastatin has also been reported to decrease coronary arterial intimal lesions while depressing immunoglobulin G alloantibody levels, suggesting a role of the humoral immune response in the development of CAV. 18 -20 Kwak and colleagues 21 have reported that statins effectively repress the induction of major histocompatibility complex class II (MHC-II) expression by interferon-␥ and do so in a dose-dependent manner.…”