Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses

Abstract

The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins.

Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia

“…AML cells upregulate cholesterol synthesis in response to cytotoxic drug exposure and it has been proposed that higher cellular cholesterol levels may improve leukaemia cell survival and impart relative resistance to therapy. 42 This mechanism is particularly interesting because of the potential to modulate cholesterol synthesis in vivo using cholesterol-lowering agents. Pgp-expressing AML cells have higher levels of HMG-CoA reductase and are more sensitive to the growth-inhibitory effect of statins than their parental cell lines.…”

Variability in responsiveness to lovastatin of the primitive CD34+ AML subfraction compared to normal CD34+ cells

“…Statins act as competitive inhibitors of the enzyme HMGCoA reductase and hence block cellular cholesterol synthesis. Consequently, a role for these cholesterol synthesis inhibitors to improve standard antileukemic treatment has been suggested [4,[6][7][8][9][10]. In the present study, we focused on a subpopulation of AML cells (CD34 + ), i.e., cells that have more in common with the more primitive leukemic progenitor/stem cell compartment [11], and questioned whether this subpopulation of cells is especially prone for the effects of lovastatin and chemotherapeutic agents.…”

“…In AML cells, an aberrant cellular cholesterol metabolism has been demonstrated, including a higher LDLR activity [4]. Interestingly, it was recently shown in vitro that cells isolated from a subgroup of AML patients demonstrated in their leukemic cells "an acute cholesterol response", i.e., a rapid increase in cellular cholesterol content in response to cytotoxic agents [5].…”

“…Interestingly, it was recently shown in vitro that cells isolated from a subgroup of AML patients demonstrated in their leukemic cells "an acute cholesterol response", i.e., a rapid increase in cellular cholesterol content in response to cytotoxic agents [5]. These AML cells were further characterized by an increased chemosensitivity upon blocking this acute cholesterol response by pretreatment of cells with a statin [4]. Statins act as competitive inhibitors of the enzyme HMGCoA reductase and hence block cellular cholesterol synthesis.…”

Clinical trials in AML of the elderly: should we change our methodology?

“…For example, a paper by List et al 5 raises the possibility that administration of daunorubicin by continuous infusion is superior to administration by bolus and that addition of cyclosporine to continuous infusion daunorubicin and ara-C is beneficial. Li et al 6 have noted that cholesterol-lowering agents increase sensitivity of AML blasts to chemotherapy presumably because these cells synthesize cholesterol as a protective mechanism following exposure to chemotherapy. The Schlenk et al trial represents another example of imaginative use of widely available therapies.…”