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Table 5. MiRNAs with effects on the anti-breast cancer activity of cyclophosphamide
MiRNA Target(s) Function Expression
let-7 - Tumor suppressor Low expression upon CP treatment
miR-9/miR-9-3p HER2, mTOR and TGF-β signaling Tumor suppressor Expression increased response to CP
miR-10b - Tumor suppressor Low expression upon CP treatment
miR-21 PTEN Oncomir High expression upon CP treatment
miR-30a transcriptional regulation Tumor suppressor Upregulation connected with better response
miR-34 - Tumor suppressor Low expression upon CP treatment
miR-143-5p B and T cell receptor and mTOR signaling Oncomir Suppression connected with better response
miR-190a BCL11A, CALCR, FOXP2, HOXC5 Tumor suppressor High expression correlated with better response
miR-195 - Oncomir High expression upon CP treatment
miR-200b-3p PLCB1, MYCN, CCND2, RERG Tumor suppressor High expression correlated with better response
miR-200c - Tumor suppressor Low expression upon CP treatment
miR-205 VEGFA, FGF2 Tumor suppressor Low expression upon CP treatment, expression
sensitizes to TAC treatment
miR-221 PUMA, ABCC1 Oncomir High expression upon CP treatment
miR-451 - Tumor suppressor Low expression upon CP treatment
miR-512-5p BCL2L2, POLD3, c-Myc Oncomir Suppression correlated with better response
miR-663 HSPG2 Oncomir Expression connected with resistance of cancer cells
miR-770-5p B and T cell receptor signaling Oncomir Suppression connected with better response
miR-3200 - Tumor suppressor Low expression upon CP treatment
ABCC1: ATP-bonding cassette C1; BCL11A: B-cell lymphoma/leukemia 11A; BCL2L2: Bcl-2-like protein 2; CALCR: calcitonin receptor;
CCND2: cyclin D2; CP: cyclophosphamide; FGF2: fibroblast growth factor 2; FOXP2: forkhead-box-protein P2; HER2: human epidermal
growth factor receptor 2; HSPG2: heparin sulfate proteoglycan 2; mTOR: mammalian target of rapamycin; MYCN: gene coding for N-Myc;
POLD3: DNA polymerase delta 3; PTEN: phosphatase and TENsin homolog; PUMA: p53 upregulated modulator of apoptosis; RERG: RAS-
like estrogen-regulated growth inhibitor; TAC: docetaxel, doxorubicin, cyclophosphamide; TGF-β: transforming growth factor β; VEGFA:
vascular endothelial growth factor A

as suppressed miR-770-5p (affected B and T cell receptor signaling) and miR-143-5p (affected B and T cell
[55]
receptor signaling as well as mTOR signaling) . A list of miRNAs involved in cyclophosphamide activity in
breast cancer is given in Table 5.

The relations between miRNAs and cyclophosphamide were also investigated in further cancer diseases.
VAC treatment (vindesine, doxorubicin, cyclophosphamide) is applied as a second-line treatment of small
cell lung cancer. The structurally simple HDAC inhibitor valproic acid increased the activity of VAC
[56]
treatment both in vitro and in vivo via induction of miR-589 and suppression of miR-575 expression . In
addition, overexpression of the oncomirs miR-27b and miR-298 led to cyclophosphamide resistance in Panc-
[57]
1 pancreatic cancer cells by inhibition of vitamin D receptor and cytochrome P3A4 (CYP3A4) . It became
evident that CYP3A4 plays a crucial role for the activation of cyclophosphamide in these cancer cells. A list
of miRNAs involved in cyclophosphamide activity in various cancers is given in Table 6.

Estramustine phosphate is applied for the treatment of advanced prostate cancer and combines the DNA-
damaging N-mustard scaffold with a tubulin polymerization inhibiting steroid (estradiol-17β-phosphate)
[58]
released upon metabolization of the drug . In prostate cancer cells, estramustine phosphate induced
[59]
apoptosis via suppression of the oncomir miR-31 . In addition, downregulation of the tumor suppressor
miR-4319, which suppresses HER2 expression, was associated with poor chemotherapy response in
prostate cancer patients and induced miR-4319 expression sensitized prostate cancer cells to estramustine
[60]
treatment . A list of microRNAs involved in estramustine phosphate anticancer activity is given in Table 7.
DACARBAZINE AND TEMOZOLOMIDE, MIRNAS AND CANCER
Dacarbazine and temozolomide [Figure 2] are valuable anticancer drugs for the treatment of melanoma and
of brain tumors such as glioblastomas (GBMs) [61,62] . Their mode of action implies the generation of highly
[63]
toxic DNA-alkylating diazomethane molecules that kill the cancer cells .