Cancer therapy's impact on lipid metabolism: Mechanisms and future avenues

Abstract

Atherosclerotic cardiovascular disease is a growing threat among cancer patients. Not surprisingly, cancer-targeting therapies have been linked to metabolic dysregulation including changes in local and systemic lipid metabolism. Thus, tumor development and cancer therapeutics are intimately linked to cholesterol metabolism and may be a driver of increased cardiovascular morbidity and mortality in this population. Chemotherapeutic agents affect lipid metabolism through diverse mechanisms. In this review, we highlight the mechanistic and clinical evidence linking commonly used cytotoxic therapies with cholesterol metabolism and potential opportunities to limit atherosclerotic risk in this patient population. Better understanding of the link between atherosclerosis, cancer therapy, and cholesterol metabolism may inform optimal lipid therapy for cancer patients and mitigate cardiovascular disease burden.

Keywords: atherosclerotic disease; chemotherapy; cytotoxic therapy; lipid metabolism; metabolic dysregulation; tumor microenvironment.

Figure 1

Host factors such as physiology and lifestyle, tumor factors that promote lipid dysregulation, and nuances of cancer therapeutics likely influence dyslipidemia in cancer. Dyslipidemia in cancer is likely due to host physiology and lifestyle, tumor processes that promote lipid dysregulation, and effects of cancer therapeutics on key points of lipid metabolism. CHIP, Clonal hematopoiesis of indeterminate potential; LXR-alpha, Liver X receptor alpha; PPAR-gamma, Peroxisome-proliferator activated receptor gamma; LDL, Low density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; ABCA-1, Adenosine triphosphate binding cassette subfamily A member 1; Created using Biorender.com.

Figure 2

Key receptors and enzymes in cholesterol physiology targeted by chemotherapeutic agents. Anthracyclines inhibit adenosine triphosphate binding cassette subfamily A member 1 (ABCA1) facilitated-transport of cholesterol from cells to high density lipoprotein (HDL), inhibit liver X receptor alpha (LXR-alpha) and peroxisome-proliferator activated receptor gamma (PPAR-gamma) nuclear receptors that transcribe ABCA-1, and increase Apolipoprotein B. Taxanes increase 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), inhibit Apolipoprotein B, and inhibit low density lipoprotein (LDL) receptor expression. Tyrosine kinase inhibitors (TKIs) inhibit LDL-receptor-related protein (LRP-1). Mammalian target of rapamycin (mTOR) inhibitors inhibit LDL receptors. Methotrexate alters expression of ABCA-1 and 27-hydroxylase. Aromatase inhibitors reduce estrogen function. Estrogen inhibits hepatic HMGCR and reduces cholesterol synthesis. Testosterone inhibits LXR-alpha and PPAR-gamma. Tamoxifen inhibits lipoprotein lipase reducing triglyceride breakdown. Apo A1, Apolipoprotein A1; SREBP-2, sterol regulatory element binding transcription factor 2; TG, Triglycerides. Created using Biorender.com.