Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias

Abstract

Key Points• FAO is a crucial metabolic pathway for leukemic cell proliferation and apoptosis.• FAO inhibitors represent a novel targeted approach for leukemia treatment.Cancer cells are characterized by perturbations of their metabolic processes. Recent observations demonstrated that the fatty acid oxidation (FAO) pathway may represent an alternative carbon source for anabolic processes in different tumors, therefore appearing particularly promising for therapeutic purposes. Because the carnitine palmitoyl transferase 1a (CPT1a) is a protein that catalyzes the rate-limiting step of FAO, here we investigated the in vitro antileukemic activity of the novel CPT1a inhibitor ST1326 on leukemia cell lines and primary cells obtained from patients with hematologic malignancies. By real-time metabolic analysis, we documented that ST1326 inhibited FAO in leukemia cell lines associated with a dose-and time-dependent cell growth arrest, mitochondrial damage, and apoptosis induction. Data obtained on primary hematopoietic malignant cells confirmed the FAO inhibition and cytotoxic activity of ST1326, particularly on acute myeloid leukemia cells. These data suggest that leukemia treatment may be carried out by targeting metabolic processes. (Blood. 2015;126(16):1925-1929

A reversible carnitine palmitoyltransferase (CPT1) inhibitor offsets the proliferation of chronic lymphocytic leukemia cells

“…Normal B lymphocytes were less sensitive to ST1326 cytotoxicity, at the doses lethal for CLL cells ( Figure 1F for CD40L+IL-4 stimulated B cells, not shown for unstimulated B cells), in line with previous observation on normal bone marrow CD34+ cells (9). Instead, cell proliferation was partly inhibited, indicating a cytostatic, rather than cytotoxic, effect of ST1326 on normal B cells.…”

“…A reversible CPT1A inhibitor, (R)-N-(tetradecylcarbamoyl)-aminocarnitine (ST1326) developed initially for diabetes treatment (6,7), was shown to decrease lymphoma (8) and leukemia (9) cell growth in preclinical studies. Though, no information is available on its effects to activated/proliferating CLL cells.…”

"Diabetes Mellitus: could the Inhibition of a Single Enzyme (CPT-1) Involved in the Beta-Oxidation Process Improve this Complex Disease?"

“…Perhaps, because of side effects this type of pharmacological approach on diabetes control could result blocking selectively liver CPT1 isoform; in fact, this isoform is also implicated in CNS control of food intake [15]. In addition, some negative aspects were already highlighted in previous studies such as steatosis [16] and apoptosis [17,18]; the latter aspect as to generate a new stream of research to anticancerogenic action due to CPT1 inhibition [19,20]. Moreover, other dangerous negative aspects of CPT blocking such as cardiac mitochondrial toxicity [21], cardiac hypertrophy [22,23] and mortality for prolonged inhibition [24] emerged in other studies; consider that diabetes is a chronic disease and as such should be treated, the continued blockade of the CPT may be contraindicated?…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…121,122 Consequently, carnitine O-palmitoyltransferase 1 (CPT-1), a protein involved in FAO, has been shown to have antiapoptotic functions in myeloid malignancies. 123 A CPT-1 inhibitor, etomoxir, 124 inhibits FAO and sensitizes leukemic cells to therapeutic challenge (Figure 2). These data provide evidence for yet another mechanism by which specific niches might shelter defined LSC subsets and promote their therapeutic resistance, thereby providing new opportunities for therapeutic intervention.…”