Table 1.
Chemotherapy-based sensitization using siRNA.
| siRNA | Target gene | Target protein | Target drug | Cancer | Observation | Ref. |
|---|---|---|---|---|---|---|
| Anti-MDR1 silencing RNA | ABCB1 | P-gp 1 also known as MDR1 | DOX or MTX | Cancer known to overexpress the MDR1 gene to develop drug resistance | siRNA downregulated MDR1 mRNA expression by 50% in breast carcinoma and osteosarcoma cell lines. It inhibited tumor cell proliferation up to 90% (P < 0.01), when co-administered with DOX or methotrexate, despite the known chemoresistance of the cell lines. siRNAs reduced the IC₅₀ of DOX and methotrexate by more than 10-fold (P < 0.01) | 14 |
| EK-specific siRNA | DEK gene (involved in chromatin reconstruction) | DEK nuclear protein | Mitoxantrone or piroxicam carboplatin | TCC in canine | This study confirmed that DEK mRNA knock-down in canine TCC cell lines could inhibit proliferation, decrease cell viability, and enhance sensitivity. The outcome suggests that DEK inhibition may support cell survival and represent a valid target for novel therapeutics or combination therapies with classical anti-cancer drugs | 15 |
| siRNA against survivin | Survivin (BIRC5) | Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5 | Gemcitabine | Human pancreatic cancer cell lines of Panc-1 and BxPC3 | It was observed that the suppression of survivin could enhance the chemosensitivity of pancreatic cancer cells to gemcitabine | 16 |
| Dual siRNA-mediated silencing of Mcl-1 and Survivin in U-937 AML cells | Myeloid cell leukaemia-1 gene (MCL-1) and survivin (BIRC5) | Myeloid cell leukaemia-1 | Etoposide | U-937 AML cells | The results confirmed that MCL-1 and survivin have a crucial role in cell survival and sensitivity of U-937 cells to etoposide | 17 |
| siRNA against RRM2 | RRM2 gene coding for the M2 subunit of ribonucleotide reductase | Ribonucleotide reductase | Gemcitabine | Pancreatic ductal adenocarcinoma cell lines PANC1, MIAPaCa2, BxPC3, and Capan2 | Simultaneous action of RRM2 silencing and gemcitabine resulted in suppressed proliferation, enhanced apoptosis and reduced metastasis. The RRM2 silencing induced gemcitabine chemoresistance in pancreatic adenocarcinoma | 18 |
| siRNA against TS1058 | TYMS | Thymidylate synthase | DOX | Human colon cancer RKO | TS1058 siRNAs were found to be effective inhibitors of TS expression and could chemosensitise colon cancer cells to DOX | 19 |
| siRNA against VEGF | VEGFA | VEGF | DOX | Hep3B cells | VEGF gene silencing was found to enhance the chemosensitivity of Hep3B cells towards DOX | 20 |
| RBFOX3-specific siRNA | RBFOX3 | RNA binding protein, FOX-1 homolog | 5-FU | Human hepatocellular carcinoma cells (SNU-449, Hep3B, Bel-7402, SNU-387, and HepG2) and human immortalized hepatic cell line MIHA | RBFOX3 gene silencing induced the cell apoptosis, inhibited migration and invasion mediated by 5-FU | 21 |
| siRNA against c-Src | SRC | c-Src tyrosine kinase also known as proto-oncogene tyrosine-protein kinase Src | Gemcitabine | PANC1, MIAPaCa2, BxPC3, and Capan2 pancreatic adenocarcinoma cell lines | c-Src played a crucial role in pancreatic adenocarcinoma chemoresistance and could be a possible target for therapeutic agents | 22 |
| EGFR siRNA | EGFR | Epidermal growth factor receptor | Cisplatin, 5-FU, and docetaxel | Human head and neck squamous carcinoma cell lines HSC-2 (JCRB0622) and SAS (JCRB0260) | EGFR gene silencing in combination with cisplatin, 5-FU, and docetaxel increased chemosensitivity of all the drugs with an increase in apoptosis | 23 |
| siRNA targeting stathmin | STMN1 | Stathmin, also known as metablastin and oncoprotein 18 | Taxanes | Human osteosarcoma cell lines (Saos-2 and MG63) | Stathmin downregulation along with Taxanes showed potent anti-cancer activity in human osteosarcomas | 24 |
| DR1-targeting siRNA (siMDR1) | MDR1 | MDR1 | PTX | Human colon cancer cell line HT-29 | MDR1 gene silencing significantly reduced the MDR1 expression in human colon CSCs, and enhanced chemosensitivity to PTX | 25 |
| Survivin-targeted siRNA | Survivin (BIRC5) | Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5 | Chemosensitivity | Androgen-independent prostate cancer cell lines PC-3, PC-3M, and DU145, and androgen-dependent prostate cancer cell lines LNCaP and 22RV1 | Silencing of survivin by RNAi inhibited cell proliferation and enhanced chemosensitivity of prostate cancer cells | 26 |
| Bmi1 siRNA | BMI1 | Polycomb complex protein BMI-1 | Cisplatin | Human endometrial cancer cell line HEC1A and Ishikawa cell lines | Duel treatment with cisplatin and BMI1 silencing resulted in a synergistic anti-cancer effect, which was higher than that was shown by cisplatin alone | 27 |
| SaOS−2/NRP-1-siRNA | NRP1 | NRP-1 | DOX | Human osteosarcoma cell SaOS-2 | NRP-1 gene silencing significantly enhanced chemosensitivity to DOX | 28 |
| siRNAs targeting Girdin | CCDC88A | Girdin | Oxaliplatin | CACO-2, D2, DLD1, HCT15, HCT116, HUTU80, SW48, SW480, SW620, SW837, CX-1, COLO205, GP2D, GP5D, HCT15, LS174T and LS180 | Girdin silencing enhances chemosensitivity of colorectal cancer cells to oxaliplatin via TOP2B down-regulation | 29 |
| siRNAs targeting RRM2 | RRM2 Gene which codes for the M2 subunit of ribonucleotide reductase | Ribonucleotide reductase | DOX | PANC-1, a pancreatic carcinoma cell line, HEK293A, a human embryonic kidney cell line | SiRRM2 was found to significantly inhibit pancreatic tumor growth alone or in combinations with DOX | 30 |
| siRNA against HIF-1α | HIF1A | HIF-1α | Gemcitabine | MIA PaCa-2 cells | The HIF-1α silencing resulted in decreased cell proliferation and enhanced chemosensitivity towards gemicitabine | 31 |
| DNMT1 siRNA | DNMT | DNA methyl transferase | Taxol | Human brain cell line GOS-3 (grade II/III oligo-dendroglioma, DMSZ, Germany) and U87-MG (grade IV glioblastoma) | siRNA mediated silencing followed by Taxol after 48 h or a combination of siRNA followed by TMZ after 24 h was found to be an effective glioma therapy | 32 |
| siRNA against TRK | NTRK1 | TrkA | PTX | Human breast cancer cell line MCF-7 | Results indicate that TrkA signalling plays a vital role in breast cancer chemo-resistance and metastasis. TrkA is an important therapeutic target | 33 |
| siRNA against TGF-β1 | TGFB1 | TGF-β1 | Temozolomide | SKOV3 cells | Results indicate that TGF-β1 silencing inhibits cancer cell growth and enhances chemosensitivity by induction of BRCA1/Smad3 signaling. | 34 |
| Plk-1-specific siRNA | PLK1 | PLK-1 | Gemcitabine | Human pancreatic adenocarcinoma cell lines AsPC-1, PANC1, and BxPC3, and the normal pancreas cell line HPDE6c7 | Duel action of Plk-1 silencing and gemcitabine chemotherapy has synergistic anti-cancer activity against pancreatic carcinoma | 35 |
| NRF2-siRNA | NFE2L2 | Nuclear factor erythroid 2-related factor 2 (NRF2) | DOX, cisplatin, and sorafenib | Human osteosarcoma cell lines 143B (CRL-8303) and MG63 (CRL-1543) | Recombinant NRF2-siRNA was effective to sensitize both 143B and MG63 cells to DOX, cisplatin, and sorafenib, which was associated with significant downregulation of NRF2-targeted ATP-binding cassette (ABC) efflux transporters (ABCC3, ABCC4, and ABCG2) | 36 |
| Survivin siRNA | Survivin (BIRC5) | Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5 | Cisplatin | HepG2 and SMMC-7721 hepatocellular carcinoma cells | Suppression of survivin expression by RNAi attenuated the malignant phenotype of hepatocellular carcinoma cells. Cells also showed decreased proliferation, increased apoptosis, and caspase-3 activity, and increased chemosensitivity to cisplatin | 37 |
| AQP-5 siRNA | AQP5 | AQP-5 | DOX | DOX Resistant breast cancer cell line MCF-7 (MCF-7/ADR) | Inhibition of AQP-5 expression may reverse the drug resistance and enhance the chemosensitivity of breast cancer cells | 38 |
| Survivin siRNA | Survivin (BIRC5) | Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5 | Cisplatin | Human pancreatic carcinoma cell line Panc-1 | The knock-down of the survivin gene expression in Panc-1 cells effectively induced apoptosis with the simultaneous increase in the cisplatin sensitivity | 39 |
| Micelle/siRNA against ABCB1 complex | ABCB1 | P-gp 1 also known as MDR1 | DOX | CF-7/ADR cell lines | siRNA and DOX-loaded micelles were found to induce apoptosis and inhibit the growth of MDR tumors | 40 |
| siRNAs against survivin | Survivin (BIRC5) | Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5 | PTX | MDR lung cancer cell line (H460/cDDP) | siRNA targeting survivin has the potential to enhance the sensitivity of drug-resistant lung cancer cells to paclitaxel | 41 |
| siRNA for DPYD or TYMS | DPYD and TYMS | Dihydropyrimidine dehydrogenase, thymidylate synthase | 5-FU | Urothelial carcinoma | Thymidylate synthase was found to play an essential role in the prognosis of upper tract urothelial carcinoma, and siRNA may be a principal-agent for urothelial carcinoma treatment | 42 |