Lipid metabolic reprogramming in colorectal cancer: Insights to mechanisms and therapeutics

Table 2 Summary of anticancer drugs targeting lipid metabolism

Target	Drug	Function	Potential side effects	Ref.
FASN	TVB-3664; TVB-3166	Promote tumor apoptosis	Not observed	Zaytseva et al[188]
ACLY	ETC-1002	Combination with IGF1R inhibitor linsitinib significantly inhibits HOXA13-mediated CRC metastasis	NA	Qiao et al[178]
ACCA	TOFA	Induces the apoptosis of cancer cells	Not toxic in mice	Wang et al[180]
ACSS	Triacsin C	Induces cytochrome c release and subsequent cell death	NA	Mashima et al[200]
SCD	Betulinic acid	Induces rapid cell death of colon cancer stem cells	NA	Potze et al[201]
SREBPs	Betulin	Induces cell cycle arrest, autophagy, and apoptosis of metastatic colorectal cancer cells	Shows an inhibitory effect on the cancer cells with non-toxic concentration towards normal cells	Han et al[202]
CD36	ABT-510; SSO	The combination of ABT-510 and bevacizumab was noted in a variety of tumor types including CRC; Inhibits FA uptake and cell growth in colorectal cancer cells cocultured with CAFs	Safe in clinical trials; NA	Luo et al[203]; Gong et al[155]
CPT1	Etomoxir	Enhances the antitumor effect of cisplatin chemotherapy on HCT116 colon cancer cells	NA	Hernlund et al[194]
HADHA	Ranolazine	Inhibits cancer cell growth, survival, and tumorigenicity in mice	Not toxic in mice	Hossain et al[204]
Cer analogs	C2-Cer; LCL-30	Inhibits proliferation and stimulates apoptosis; Induces cell death by reducing the mitochondrial membrane potential	NA; Not found to be toxic in freshly hepatocytes (selective toxicity)	Ahn and Schroeder[205]; Dindo et al[206]
Acid ceramidase	LCL-521	Decreases viability of colon cells	NA	Tirodkar et al[207]
PLD	FIPI	Decreases cancer cell proliferation and migration promoted by stromal fibroblasts	NA	Majdop et al[208]
SphK1	PF-543; RB005	Inhibits CRC cell proliferation. Inhibits CRC cell growth and proliferation	NA; NA	Ju et al[155]; Shrestha et al[209]
SphK2	ABC294640	Induces CRC cell growth inhibition and apoptosis; inhibits colitis-driven colon carcinogenesis	No systemic toxicity	Xun et al[210]; Chumanevich et al[211]
S1PR modulators	FTY-720	FTY720 induces apoptosis in colorectal cancer cells via PP2A activation. FTY720 exhibits an additive effect with 5-fluorouracil, SN-38, and oxaliplatin in standard chemotherapy in patients with CRC	Cytotoxic effects of FTY720 are markedly reduced in normal colon cells	Cristóbal et al[212]
HMGCR	Statins	Decrease cancer mortality and promote longer survival, according to retrospective clinical analysis	NA	Poynter et al[213]
OSC	R048-8071	Dampens cell proliferation, increases apoptosis and decreases cell migration	NA	Maione et al[214]
ACAT1	Avasimin	Increases apoptosis with no clear cytotoxicity	Safe in mouse models of avasimin treatment	Lee et al[215]
LXR	SR9243	Represses lipogenesis and glycolysis in cancer cells; induces apoptosis	Not toxic	Flaveny et al[216]

FASN: Fatty acid synthase; ACLY: Adenosine triphosphate-citrate lyase; ACCA: Acetyl-CoA carboxylase-A; SCD: Stearoyl-CoA desaturase; SREBP: Sterol regulatory element-binding protein; C2-Cer: C2 ceramide; CD: Cluster of differentiation; CPT: Carnitine palmitoyl transferase; PLD: Phospholipase D; SphK: Sphingosine kinase; SIPR: Sphingosine-1-phosphate receptor; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; OSC: Oxido squalene cyclase; LXR: Liver X receptor; FTY-720: Fingolimod hydrochloride; ETC-1002: Bempedoic acid; TOFA: 5-tetradecyloxy-2-furoic acid; SSO: Sulfo-N-succinimidyloleate; IGF1R: Like growth factor 1 receptor; CRC: Colorectal cancer; FA: Fatty acid; CAF: Cancer-associated fibroblast; PP2A: Protein phosphatase 2A; NA: Not appliable.