Table 1.
Targeting lipid or cholesterol metabolism for cancer treatment.
| S. No | Cancer types | Drug /Inhibitors Under Investigation | in vitro/ in vivo/Clinical Studies | Cell line/ Animal model/Patient Information | Outcome of Treatment/ Effect / Treatment modalities | Ref. |
|---|---|---|---|---|---|---|
| 1 | Colon | Lovastatin | in vitro & in vivo | SW480, SW620 cellsBalb/c mice | Decreases MCA-26 tumor colonies in the liver of Balb/c mice compared to untreated mice | [35] |
| 2 | Colon Lung Breast | Liposomal Doxorubicin and Simvastatin | in vitro | HT29-dx (drug-resistant), HT29, MCF-7, A549 cells | Combination treatment shows better anticancer efficacy in multidrug-resistant tumor cells, without cardiomyocytes toxicity | [36] |
| 3 | Colon | Atorvastatin & Phloretin | in vitro | SW620 and HCT116 cells | The synergistic effect resulted in apoptosis and cell cycle arrest at the G2/M checkpoint. Combined treatment enhanced the anti-cancer activity of Atorvastatin at a relatively low dosage | [203] |
| 4 | Colon | Long-circulating Liposomal Simvastatin (LCL-SIM) | in vitro & in vivo | C26 cell and Balb/c mice | Anti-angiogenic and anti-inflammatory Antitumor efficacy | [204] |
| 5 | Colon | Nanoliposomal anti PCSK9 | in vivo | CT26 cells and Balb/c mice | Inhibits tumor growth and increases survival | [217] |
| 6 | Colon | SREBP 1 & SREBP 2Knockdown | in vitro & in vivo | DLD1 and HCT116 cellsNOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice;Pt130 cells | Knockdown decreased fatty acids level. Silencing of SREBP1 or SREBP2 expression also decreases mitochondrial respiration, glycolysis, as well as fatty acid oxidation. Inhibit xenograft colon tumor growth in vivo | [218] |
| 7 | Colon | Pioglitazone (PPAR gamma) agonist | in vivo | C57BL/6-ApcMin /+mice | A decrease in intestinal polyps was observed in Min mice, 63–9% lesser than the control value. | [221] |
| 8 | Colon | HDL mimetics: L-4F (an apolipoproteinA-I mimetic peptide) & G*(an apolipoprotein J mimetic peptide) | in vivo | CT26 cellBALB/c mice | HDL mimetics decrease lysophosphatidic acid (LPA), a serum biomarker of colon cancer in mice.L-4F reduced size and number of polyps in APC (min/+) mice | [222] |
| 9 | Prostate | Ezetimibe | in vivo | LNCaP cellsSCID mice | Inhibit tumor angiogenesis and decrease tumor growth | [90] |
| 10 | Prostate | Statin | Clinical | 6655 participants (men) | Statin decreases chronic inflammation and lowers the risk of advanced prostate cancer | [199] |
| 11 | Prostate | Avasimibe, Sandoz 58–035 &shRNA (ACAT-1) | in vitro | PC-3 and LNCaP-HP cells.Athymic nude mice | Targeting cholesterol esterification pathway inhibits proliferation of prostate cancer cells both in vitro and in vivo | [225] |
| 12 | Hepato-cellular carcinoma | Eicosapentaenoic acid (EPA) & Lovastatin | in vitro | HepG2 cells | Combination treatment regulates HMGCoA reductase and LDL receptor gene expression in the HepG2 cell line. Synergistically inhibits cancer cell proliferation | [201] |
| 13 | Hepato-cellular carcinoma | Naringenin (NGEN)(High Cholesterol Diet) | in vivo | Rat | NGEN decreased plasma fatty acid composition, hepatic pro-inflammatory mediators, and the expression of tumor necrosis factor-α, interleukin-6, interleukin-1β, inducible nitric oxide synthase, and matrix metalloproteinases (MMP-2, 9) | [220] |
| 14 | Hepato cellular carcinoma, Breast | Methyl-β-cyclodextrin (MCD), Doxorubicin | in vitro & in vivo | MCF-7, Hepa1–6C57Bl/6 | MCD sensitize MCF-7 and Hepa1–6cells to Doxorubicin | [224] |
| 15 | Pancreatic ductal adeno-carcinoma (PDAC) | LDLR shRNA | in vitro & in vivo | Pdx1-Cre, Ink4a/ Arffl/fl; LSL-KrasG12DPK4A cell lines | Decreases cholesterol uptake sensitized PDAC to gemcitabine | [28] |
| 16 | Pancreatic ductal adeno-carcinoma (PDAC) | Simvastatin, Lovastatin, Atorvastatin, Pravastatin, Rosuvastatin | Clinical | 2142 patients | Statin lowers the risk of mortality in pancreatic cancer patients independent of cholesterol level | [211] |
| 17 | Pancreatic | Simvastatin, Atorvastatin, Rosuvastatin, Pravastatin, Fluvastatin | Clinical | 1761 patients with pancreatic adeno-carcinoma | The use of simvastatin and atorvastatin increases the survival of non-metastatic pancreatic cancer patients | [212] |
| 18 | Pancreatic | Simvastatin | in vivo | Mice model -LsL-Kras (G12D); Pdx1-Cre and LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre | Simvastatin acts as a chemopreventive agent as well as inhibits pancreatic cancer formation in mice | [213] |
| 19 | Pancreatic | Zoledronic acid (inhibitor of farnesyl diphosphate synthase) | in vitro & in vivo | Panc-1, BxPC3, L3.6pl, UN-KPC-961 cell lines. LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx-1-Cre (KPC) mouse model | Inhibition of farnesyl diphosphate synthase involved in cholesterol biosynthesis radio sensitized pancreatic cancer cell lines. | [228] |
| 20 | Pancreatic ductal adenocarcinoma (PDA) | JQ1 (BET inhibitor), Atorvastatin | in vitro | PANC-1, AsPC-1, MIA PAC-2 cells | Combination treatment of JQ1 and atorvastatin inhibits PDA cell proliferation in vitro conditions. | [248] |
| 21 | Melanoma | Methyl-β-cyclodextrin (MCD), Tamoxifen | in vitro & in vivo | A375, B16F10 and B16F1 cell lines. | MCD sensitizes melanoma cells to tamoxifen | [198] |
| 22 | Epithelial Ovarian cancer (EOC) | Statin | Clinical | 2040 EOC cases2100 cases without disease | 32% decrease in the risk of ovarian cancer in statin users in comparison to non-statin user females | [205] |
| 23 | Ovarian | Simvastatin | in vitro, in vivo & Clinical | Hey and SKOV3 cells;K18-gT121+/- p53fl/fl Brca1fl/fl (KpB) mouse model | Simvastatin decreases ovarian cancer cell proliferation and tumor growth. Induced G1 cell cycle arrest and apoptosis | [249] |
| 24 | Ovarian | Simvastatin, Lovastatin, Fluvastatin, 25-hydroxycholesterol, 22(S)- hydroxycholesterol, 22(R)-hydroxycholesterol | in vitro | SKOV-3 and ES-2, OVCAR-8 | Oxysterol potentiate statin treatment by inhibiting SREBP-2 | [250] |
| 25 | Ovarian | Methyl-β-cyclodextrin (MCD) | in vitro & Clinical | PA-1, OVCAR-3, and SKOV-3 cells | MCD sensitizes cisplatin-resistant ovarian cancer cells to cisplatin. | [25] |
| 26 | Ovarian | Avasimibe, Cisplatin | in vitro | H-6036, OC-314, and SKOV-3 cells | Inhibition of ACAT-1 enhances the chemosensitivity of cisplatin to ovarian cancer cells | [177] |
| 27 | Ovarian | HSP27 and HER2 inhibitor encapsulation into LDL | in vitro | SKOV3 | Treatment of LDL encapsulated HSP27 and HER2 inhibitor inhibits SKOV3 proliferation | [251] |
| 28 | Breast | Methyl-β-cyclodextrin (MCD),Carboplatin, 5-flurouracil | in vitro & in vivo | MCF-7, MDA-MD-231 | MCD sensitize breast cancer cells to Carboplatin and 5-flurouracil | [223] |
| 29 | Breast | Paclitaxel-cholesterol complex (PTX-CH Emul) | in vitro & in vivo | MCF7, MDA-MB-231 cells | PTX-CH Emul shows more antineoplastic effect on TNBC cells (MDA-MB-231) as compared to non-TNBC (MCF7). | [234] |
| 30 | Breast | Atorvastatin | Clinical (rando-mise) | 63 Women, (Age 35–50)16 (25%) Women withdrew. | Significant increase in serum IGF-1 in the statin group but no effect of atorvastatin on Mammographic Density (MD) | [235] |
| 31 | Breast | Simvastatin & MBCD (cholesterol depleting drug) | in vitro | RAW264.7 and MCF-7 cells | Combination treatment prevents breast cancer-induced osteoclast activity. | [236] |
| 32 | Breast | Cholesterol lowering medication, Tamoxifen & Letrozole | Clinical | 8010 (Postmenopausal women) | Cholesterol lowering medication during adjuvant endocrine therapy may prevent the recurrence of hormone receptor-positive breast cancer. | [237] |
| 33 | Lung and Breast | Cepharanthine, Cisplatin | in vitro & in vivo | Human umbilical Vein endothelial cells (HUVEC) A549, MDA-MB-231 & HEK293T cells.NOD/SCID mice, Transgenic zebrafish line Tg (fli1a:EGFP)y1 | Blocking cholesterol trafficking with cepharanthine inhibits angiogenesis and sensitizes breast and lung cancer cells to chemotherapy. | [238] |
| 34 | Lung | Cholesterol Cisplatin, Oxaliplatin, Carboplatin Pravastatin and Nicardipine | in vitro & Clinical | A549 cell64 patients | Patients showing quick chemoresistance have elevated serum cholesterol levels and found to have upregulated ABCG expression in their tumors. The use of ABCG blocker (nicardipine) increases the efficacy of platinum base drugs in vitro conditions. | [229] |
| 35 | Lung | All-trans retinoic acid (ATRA), DOTAP/cholesterolliposomes & DSPC/cholesterol liposomes | in vitro | A549 cells | Cationic liposome (DOTAP/cholesterol) incorporation with ATRA increases apoptotic cell death of A549. | [239] |
| 36 | Lung | Statin | Clinical | 483,733 patients | The use of statin reduces lung cancer risk by 55% irrespective of race, age group, diabetic, alcoholic, or even smoking. | [240] |
| 37 | Lung | Cholesterol oxidaseBordetella species cholesterol oxidase (COD-B) | in vitro & in vivo | A549 and SPC-A-1 cellsBALB/c nude mice | COD-B oxidizes membrane cholesterol thereby decreasing cholesterol content and increases ROS. COD-B causes apoptosis of lung cancer cells by interfering with AKT and ERK pathway. | [241] |
| 38 | Lung | Betulin, Fatostatin, 25-HC & Gefitinib | in vitro & in vivo | A549 and PC9 cellsBALB/c SCID mice | Combination treatment of SREBP inhibitor with EGFR inhibitor (Gefitinib) increases the non-small cell lung cancer death in comparison to alone treatment. | [242] |
| 39 | Lung | Pirarubicin, Ellipticine & MCD | in vitro | A549 and CHO-K1 cells | Membrane cholesterol depletion with MCD enhances drug uptake of pirarubicin but not Ellipticine in A549 and CHO-K1 cells. | [243] |
| 40 | Lung | Zaragozic acids | in vitro & in vivo | C57Bl/6 CD45.1 or CD45.2 and NOD–SCID mice RMA and LLC cells | Zaragozic acids, an inhibitor of the downstream mevalonate pathway enhances the antitumor effects of active and adoptive immunotherapy. Increases overall survival of tumor-bearing mice on treatment with zaragozic acids and TAA-loaded DCs. | [244] |
| 41 | Lung | Gemcitabine-cholesterol (Gem-Chol) liposome | in vitro & In vivo | H22 and S180 tumor xenograftWistar male rats | Gem-Chol conjugate enhances the efficacy of Gemcitabine. | [245] |
| 42 | Lung | siRNA/curcumin loaded, Cholesterol conjugated chitosan | in vitro | A549 cell | Cholesterol conjugated chitosan can be used for hydrophobic drug delivery. Cellular uptake of drug is more efficient in Cholesterol conjugated chitosan. | [246] |
| 43 | Lung | LXR agonistT0901317,Gefitinib | in vivo & in vitro | A549 cellHCC827–8–1 (gefitinib-sensitive) cells | Combination treatment of T0901317 & gefitinib inhibits migration and invasion of lung cancer. | [247] |
| 44 | Gastric | Simvastatin | in vitro | MKN45 and MGC803 cells | Inhibits migration, invasion, proliferation, and induced apoptosis in gastric cancer cells by interfering with YAP and β-catenin activity. | [206] |
| 45 | Gastric | Simvastatin | in vitro & Clinical | AGS, ATCC CRL 1739 cells | Statin reduces the incidence of gastric cancer by attenuating Helicobacter pylori CagA translocation | [202] |
| 46 | Stomach | Statin | Clinical | 17,737 statin users and 13,412 statin non-user | The use of statin decreases the incidence of stomach cancer on hypercholesterolemic individuals. | [252] |
| 47 | Blood (chronic myelogenous leukemia) | Avasimibe, Imatinib | in vitro & in vivo | K562R (imatinib-resistant) | Avasimibe sensitized K562R to imatinib | [226] |
| 48 | Blood (lymphoblasts and myeloma cells) | Lovastatin Simvastatin Cerivastatin Leverkusen, Atorvastatin | in vitro | Jurkat, CEM, IM9, U266 cell MCC-2 | Statin induces mitochondrial apoptosis pathway in human T, B, and myeloma tumor cells causing cell death | [200] |
| 49 | Blood (leukemia and lymphoma) | Simvastatin, Atorvastatin, Rosuvastatin, Fluvastatin,Venetoclax | in vitro, in vivo, & Clinical | AML cells (OCI-AML2, OCI-AML3, MOLM13), DLBCL cells (OCI-LY8, SU-DHL4).C57BL/6 N mice | Statin increases the pro-apoptotic activity of Venetoclax (B cell lymphoma-2 inhibitor) in primary leukemia and lymphoma cells | [253] |