Table 2.
Summary of combination studies targeting DNMTs in BC.
| Drug | Model | Concentration | Treatment Scheme | Effects | Year | Reference |
|---|---|---|---|---|---|---|
| 5-Aza and FK228 | 253J, T24, TCCSUP, UMUC3, and WH | 5-aza 1–25 µM FK228 0.25-5 ng/mL |
3 days | ↑ Apoptosis ↓ G2/M cell population |
2007 | [147] |
| DAC and cisplatin | 253J, RT112, T24, and TCCSUP | DAC 0.1–8 µM Cisplatin 0.25–2 µg/mL |
3 days | ↑ Cell arrest at G2/M ↓ Proliferative ability ↑ Apoptosis ↑ Susceptibility to cisplatin |
2008 | [160] |
| 5-Aza, cisplatin, and docetaxel | T24, TCCSUP, and UMUC3 | 5-Aza 0.6 µM Cisplatin 1 µM Docetaxel 5 nM |
5-Aza for 72 h followed by cisplatin or docetaxel for 72 h | ↑ Cell toxicity with combined treatment | 2011 | [150] |
| 5-Aza and TSA | K9TCC, K9TCC-PU-Nk, and K9TCC-PU-Sh | 5-Aza 1–50 µM TSA 0.5 µM |
2 days | ↑ p16 expression ↓ Cell number ↓ Cyclin D1, p21, pRb, survivin, and PARP expression |
2013 | [148] |
| DAC, TSA, cisplatin, and gemcitabine | T24 | Gemcitabine 2.5 µM Cisplatin 1.25 µM DAC 10 µM TSA 300 nM |
Gemcitabine and cisplatin for 48 h followed by DAC for 48 h and TSA for 6 h | ↑ Apoptosis ↓ Cell proliferation ↑ DNA fragmentation ↑ CASP-3 mRNA levels ↑ GSK3β mRNA levels ↑ Canonical Wnt pathway ↓ BCL2L1 mRNA levels |
2014 | [156] |
| DAC, cisplatin, doxorubicin, etoposide, and vinblastine | 96-1, 97-1, RT4, and SW1710 | DAC 100 nM Cisplatin 0.3–3000 µM Etoposide, vinblastine, and doxorubicin 0.1–1000 µM |
DAC for 120 h followed by chemotherapeutic drugs for 48 h | ↓ IC50 of chemotherapeutic drugs with combined treatment | 2016 | [152] |
| DAC, cisplatin, and doxorubicin | HT1376 and T24 | DAC 1 and 5 µM Cisplatin and doxorubicin 1–10 µg/mL |
DAC for 72 h followed by cisplatin or doxorubicin for 72 h | ↑ Cell toxicity ↑ RASSF1A expression Hippo pathway activation |
2018 | [151] |
| DAC, cisplatin, and gemcitabine | 5637 and SCaBER | DAC 100 nM Cisplatin 100–150 ng/mL Gemcitabine 2–150 ng/mL |
Daily for 72 h | ↑ Apoptosis ↓ Ratio of CD44v6+ and ALDH+ cells ↑ SOCS3 expression |
2019 | [155] |
| BNN-induced mouse model | Cisplatin 2.5 mg/kg Gemcitabine 120 mg/kg DAC 0.05–0.2 mg/kg |
Cisplatin weekly for 3 weeks Gemcitabine weekly for 3 weeks DAC once daily for 5 consecutive days and 3 times per week |
↓ Number of invasive tumors ↓ Cancer cells proliferation ↑ Apoptosis ↓ KRT14+ expressing cells ↓ SOX2+ expression cells ↓ STAT3 phosphorylation |
|||
| Patient sample-derived xenografts | ||||||
| DAC and cisplatin | CR-T24 and T24 | DAC 2 µM Cisplatin 1 µg/mL |
DAC for 48 h followed by cisplatin for 24 h | ↓ Colonies formation ↑ Tap73 expression ↑ Cisplatin response |
2019 | [161] |
| CM-272 and pembrolizumab |
Quadruple-knockout transgenic mouse model of metastatic BC. Cre-dependent inactivation of Pten, Trp53, and Rb1 specifically in urothelial cells (AdK5Cre) of Rbl1-deficient mice |
CM-272 5 mg kg−1
Anti-PD-L1 200 μg per injection |
Treatment of mice started at the time of tumor detection. CM-272 intraperitoneally 5 days per week. Anti-PD-L1 once a week for a total of 3 injections. |
Extensive immune infiltrations comprising CD3+, CD8+, and NK cells Low number of animals showing tumor or metastasis evidence. Prolonged anti-tumor effect without any treatment |
2019 | [159] |
| DAC and entinostat | J82, J82CisR, HBLAK, and RT112 | DAC 0.1 and 1 µM Entinostat IC50 according to cell line |
DAC for 48 h followed by entinostat for 48 h | Growth inhibition ↑ Apoptosis ↑ Cell arrest in G2/M transition ↑ FoxO1 expression ↑ BIM and p21 expression ↓ Survivin expression |
2020 | [149] |
Abbreviations: 5-aza—5-azacytidine; CASP-3—caspase 3; DAC—decitabine; FoxO1—forkhead box O1; GSK3β—glycogen synthase kinase 3 beta; KRT14—keratin 14; PARP—poly(ADP-ribose) polymerase; RASSF1A—Ras association domain family 1 isoform A; SOCS3—suppressor of cytokine signaling 3; SOX2—SRY-box transcription factor 2; STAT3—signal transducer and activator of transcription 3; Tap73—tumor protein P73; TSA—trichostatin A. ↑—increase, ↓—decrease.