Table 2.
miRNAs target by metabolic-drugs or miRNAs related to therapy resistance.
| Drug | Druggable miRNA/Therapy-resistance miRNA* | Cancer | References |
|---|---|---|---|
| Targeting glucose metabolism | |||
| Metformin | ↑let-7a, let-7b, miR-26a, 101, 192, 200b and 200c. Over-expression of miR-26a decrease cancer stem-cells markers, an enhanced apoptosis rate. Let-7b re-expression blocks stem cells features | PC BRCA Oral Renal | (170–174) |
| ↑miR-34a in obese mice reducing its putative targets (Notch, Slug, Snail) ↑miR-34a which in turn restrict Sirt1/Pgc1α/Nrf2 signaling pathway and decrease proliferation rates | PC | (175) (176, 177) | |
| ↓miR-27a which AMPKα and ↑miR-193 family that increased AMPKα and decrease FASN levels, resulting in limiting mammospheres phenotype | BRCA | (178, 179) | |
| Combined treatment of metformin + FuOx ↓miR-21 and ↑miR-145, that suppress β-catenin and c-Myc signaling expression colon cancer cells | CRC | (180) | |
| ↑miR-141, 200a, 205 and 429 inhibiting EMT, thus, modulating metastatic traits | GC | (181) | |
| ↑mir-124, 182, 27b, let7b and ↓miR-221 and 181a; inhibiting cell proliferation | CLC | (182) | |
| ↑miR-192-5p, 584-3p, and 1246; suppressing cell motility and cell cycle | M | (183) | |
| ↑DROSHA, modulate the miRNA biogenesis, to affect these miRNAs expression | CLC | (182) | |
| ↓miR-222 resulting in enhance abundance of p27, p57, and PTEN ↓miR-222 resulting in enhance abundance of p27, p57, and PTEN | Lung | (184) | |
| ↑DICER expression and miR-33a that targets c-MYC | BRCA | (185) | |
| ↓miR-146a, 100, 425, 193a-3p and 106b involved in cell migration, invasion and proliferation | PCA | (186) | |
| ↑miR-192-5p, miR-584-3p, and miR-1246 enhance EFEMP1 and SCAMP3 downmodulation favoring the suppression of cancer cell motility and growth through G2/M cell cycle arrest and cell apoptosis | M | (183) | |
| RS:↑miR-21 ↓miR-21 and ↑miR-145 over combined treatment with 5-fluorouracil and oxaliplatin, that suppress β-catenin and c-Myc expression, and consequently reduce cell growth and sphere formation ↓miR-21-5p in cell lines model, xenograft murine model and in tissue from human patients. Since also the pre-miRNA sequence is down-modulated the modulation seems to be at the transcriptional level. Functional reduction of miR-21-5p allow the expression of upstream activators of the AMPK, CAB39L and SESN1 | CRCBRCA | (187) (180)(188) | |
| Dichloroacetate (DCA) | Promising therapeutic agents to ↓miR-210 | Cancer | (189) |
| ↑miR-375 resulting in anti-proliferating effects | PCA | (190) | |
| CPI-613 | May improve miR-497-5p,−449a,−25-3p,−6838-5p,−520d-3p that down-modulates the expression of Cyclin D3, E1, E2, F, A2, B1 and CDK2 genes of BxPC-3 | Cancer | (189) |
| Targeting FA metabolism | |||
| Statins | Lovastatin upregulated miR-33b expression, reduced cell proliferation and impaired c-Myc expression | MB | (191) |
| Simvastatin: inhibits the growth of human CRPC cells by suppressing NF-κB and LIN28B and ↑let-7 miRNA family | PCA | (192) | |
| Simvastatin: ↓miR-34a, which regulates the NAD+-dependent histone deacetylase SIRT1. ↑miR-612, which is known to reduce stemness | BRCA, PCA, OsC | (193) | |
| Simvastatin is an activator of miR-192 which subsequently led to suppressed proliferation, migration and invasion | CRC | (194) | |
| Atorvastatin: ↑miR-182 that targets the anti-apoptotic Bcl-2 and p21 | PCA | (195) | |
| ↑miR-140-5p activating the transcription factor NRF1 that reduced cell proliferation and induced apoptosis | BRCA | (196) | |
| Fluvastatin: ↓miR-140-3p-1 and its downstream pathway such as cell growth | BRCA | (197) | |
| Statin: ↑miR-33a promoting a proliferation inhibitory effect | PCA | (198) | |
| lovastatin: ↓miR-133a promoting GCH1 important for endothelial nitric oxide synthase | Cancer | (199) | |
| Rapamycin | Rapamycin-dependent miRNA: ↑miR-29b, 21, 24, 221, 106a, and 199a | Renal | (200) |
| ↑let-7, miR-125a,−125b,−21, and−26a. Rapamycin is mediated by let-7 family with anti-proliferative effects | Renal | (201) | |
| *RS: miR-21 supports mitochondrial function and adaptation to rapamycin | Renal | (200) | |
| Long-term rapamycin treatment RS: ↑MYC that results in ↑miR-17–92 | Brain | (201) | |
| Aspirin and non-steroidal anti-inflammatory agents | ↑miR-98 that targets WNT1, suppressing cell proliferation | Lung | (202) |
| Sulindac drug: ↓miR-9,−10b,−17, and−21 by suppressing NF-κB-mediated transcription of miRNAs | BRCA CRC | (203) | |
| ↓miR-21 decreasing cell proliferation and invasion upon inactivation of β-catenin/TCF4 signaling | CRC | (204) | |
| ↑let-7 by decreasing the miRNA-sponge H19, resulting in the down-modulation Hypoxia-inducible factor 1α reducing l PDK1, attenuating glycolysis | BRCA | (195) | |
| Celecoxib: ↑miR-29c supress the oncogen MCL-1 reducing apoptosis | GC | (205) | |
| TVB-2640 | miR-15 and miR-16-6: Inhibition of FASN: Agonist effect | BRCA | (206) |
| Targeting lactate metabolism: LDHA inhibitors | |||
| AZD3965 | miR-342-3p: Inhibition of the monocarboxylate transporter MCT1: Agonist effect | BRCA | (103) |
| Antimetabolite chemotherapeutic agents | |||
| Methotrexate (MTX) | *RS: ↑miR-24 SNPresults | (207) | |
| *RS: ↑miR-140 | OsC, CRC | (208) | |
| *RS: ↑miR-215 modulated DTL, a cell cycle-regulated gene | OsC, CRC | (209) | |
| Capecitabine | ↑miR-125b-5p ↑miR-137 | Cancer | (189) |
| 5-Fluorouracil | ↓Relevant oncogenes such as miR-210 | HCC CRCOsC | (208, 210, 211) |
| ↑Relevant tumor suppressor miRs: let-7 family, miR-15b,−16,−23a,−23b, and−200c | BRCA | (189) | |
| *ES: ↑miR122 through the inhibition of M2 splice isoform of pyruvate kinase (PKM2) in vitro and in vivo | CRC | (212) | |
| *RS: ↑miR-21 and−221 | BRCA | (213) | |
| *RS: ↑miR-21,−34,−140 | HCC CRCOsC | (212) | |
| Gemcitabine | May impact the expression of 56 relevant miRNAs such as miR-200,−205,−27a,−27b, and let 7 family | Cancer | (214, 215) |
| *ES: ↑microRNA-218 by inhibiting the secretion of HMGB1 by PANC-1 cells and the PI3K/Akt pathway | PC | (212) | |
| *RS: ↑miR-21,−34,−140 | PC | (214, 215) | |
| Targeting glutamine metabolism | |||
| Pegylated arginine deiminase (ADI-PEG) | Bioengineered pre-miR-1291 processed to high levels of mature miR-1291. *ER: ↑miR-1291 increases sensitivity to ADI-PEG (trough modulation of ASS1 and GLUT1) | PC | (216) |
*
Therapy-resistance miRNA. ↑, over-expression; ↓, down-regulation. Therapy-resistance miRNA: RS, reduce sensitivity; ES, enhanced sensitivity. Cancer: BRCA, breast cancer; CRC, colorectal cancer; PCA, prostate cancer; PC, pancreatic cancer; HCC hepatacarcinoma; CLC, cholangiocarcinoma; MB, medulloblastoma; OsC, osteosarcoma; GC, Gastric; M,Melanoma.