Targeting of Mevalonate-Isoprenoid Pathway in Acute Myeloid Leukemia Cells by Bisphosphonate Drugs

Abstract

Metabolic reprogramming represents a hallmark of tumorigenesis to sustain survival in harsh conditions, rapid growth and metastasis in order to resist to cancer therapies. These metabolic alterations involve glucose metabolism, known as the Warburg effect, increased glutaminolysis and enhanced amino acid and lipid metabolism, especially the cholesterol biosynthesis pathway known as the mevalonate pathway and these are upregulated in several cancer types, including acute myeloid leukemia (AML). In particular, it was demonstrated that the mevalonate pathway has a pivotal role in cellular transformation. Therefore, targeting this biochemical process with drugs such as statins represents a promising therapeutic strategy to be combined with other anticancer treatments. In the last decade, several studies have revealed that amino-bisphosphonates (BP), primarily used for bone fragility disorders, also exhibit potential anti-cancer activity in leukemic cells, as well as in patients with symptomatic multiple myeloma. Indeed, these compounds inhibit the farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway, reducing isoprenoid formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. This, in turn, inhibits the prenylation of small Guanosine Triphosphate-binding proteins, such as Ras, Rho, Rac, Rab, which are essential for regulating cell survival membrane ruffling and trafficking, interfering with cancer key signaling events involved in clonal expansion and maturation block of progenitor cells in myeloid hematological malignancies. Thus, in this review, we discuss the recent advancements about bisphosphonates' effects, especially zoledronate, analyzing the biochemical mechanisms and anti-tumor effects on AML model systems. Future studies will be oriented to investigate the clinical relevance and significance of BP treatment in AML, representing an attractive therapeutic strategy that could be integrated into chemotherapy.

Keywords: AML; bisphosphonates; mevalonate pathway; protein isoprenylation; small GTPases.

Figure 1

Metabolic reprogramming in cancer involves glucose and cholesterol metabolism alterations. The energy production from fats has the same weight as alterations in glucose metabolism in supporting the viability of cancer cells.

Figure 2

Schematic overview of the mevalonate pathway, isoprenoid/sterol biosynthesis and prenylation of proteins. Statins block HMGCR activity. Nitrogen-containing bisphosphonates (N-BPs) inhibit FDPS activity. Farnesyl transferase inhibitors (FTIs) and geranylgeranyl transferase inhibitors I/II (GGTIs I/II) inhibit protein farnesylation and geranylgeranylation, respectively.

Figure 3

Schematic pathway for the small GTPase post-translational modification of prenylated proteins. Prenyltransferases attach farnesyl or geranylgeranyl lipids, derived from isoprenoid/sterol biosynthesis, to the cysteine within the C-terminal CAAX motif of small GTPase proteins, such as Ras. Nitrogen-containing bisphosphonates (N-BPs) are used to inhibit the prenyltransferases activity. The prenylated proteins undergo further modification on the cytosolic surface of the ER, by intrinsic ER membrane proteins. In particular, Ras CAAX prenyl protease 1 (RCE1) cleaves the AAX, and the resulting free carboxyl group of the prenyl cysteine moiety is methylesterificated by isoprenylcysteine carboxyl methyltransferase (ICMT), in order to target prenylated proteins to cell membrane. ER: Endoplasmic Reticulum; PM: Phospholipid Membrane.

Figure 4

Biological effects of bisphosphonates on acute myeloid leukemia (AML). (A) Structural similarities between endogenous inorganic pyrophosphate and bisphosphonate. (B) The inhibitory effects of early bisphosphonates, second- and third-generation bisphosphonates on osteoclast differentiation/function via blocking the activity of farnesyl pyrophosphate synthase (FDPS). (C) The anti-tumor effects of zoledronic acid on acute leukemic cells.