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Page 4 Biersack. Cancer Drug Resist 2019;2:1-17 I http://dx.doi.org/10.20517/cdr.2019.09

Table 1. MiRNAs with effects on the anticancer activity of chlorambucil
MiRNA Target Function Expression in cancers/tissues
miR-34a p53 Tumor suppressor Suppressed in resistant CLL
miR-17-92 cluster PTEN Oncomir Upregulated in resistant B-cell lymphoma
miR-210 GPD1L Oncomir Upregulated in triple-negative breast cancer
CLL: chronic lymphocytic leukemia; GPD1L: glycerol-3-phosphate dehydrogenase 1L; PTEN: phosphatase and TENsin homolog

Table 2. MiRNAs with effects on the anticancer activity of melphalan
MiRNA Target(s) Function Expression in cancers/tissues
let-7b Myc, Ras, CCND1 Tumor suppressor Exosomal let-7b upregulated in sensitive MM
miR-15a/16 - Tumor suppressor Suppressed in resistant myeloma
miR-18a HIF1α Tumor suppressor Exosomal miR-18a upregulated in sensitive MM
miR-221-222 family PUMA, ABCC1 Oncomir Upregulated in resistant MM
miR-451 MDR1 Oncomir Suppressed in resistant MM
ABCC1: ATP-binding cassette C1; CCND1: cyclin D1; HIF1α: hypoxia-inducible facter 1-α; MDR1: multidrug resistance gene 1; MM: multiple
myeloma; PUMA: p53 upregulated modulator of apoptosis

Clinical sensitivity to cyclophosphamide is strongly correlated with the ability of cancer cells to induce
[33]
apoptosis upon DNA damage . Due to its significance in cancer therapy the relations between miRNAs
and cyclophosphamide is well studied, in particular, in lymphoma [34,35] . Upregulation of circulating
oncogenic miR-125b and miR-130a was determined in B-cell lymphoma samples from patients treated
with cyclophosphamide-based chemotherapy . In diffuse large B-cell lymphoma (DLBCL, the most
[36]
common non-Hodgkin lymphoma type) treated with R-CHOP (rituximab, cyclophosphamide, adriamycin,
vincristine, and prednisone), increased miR-181a expression prolonged progression free survival (PFS) by
suppression of FOXP1 and O6-methylguanine DNA methyltransferase (MGMT) while increased miR-18a
levels led to shorter overall survival (OS) and high miR-222 expression to shorter PFS . MiR-93 (targets:
[37]
p21, BCL2L11), miR-221 and miR-222 (target: p27) were upregulated in DLBCL patients with poor outcomes
after cyclophosphamide-based therapies . Knockdown of the well-known oncomir miR-21 sensitized
[38]
[39]
DLBCL cells to CHOP treatment by upregulation of PTEN . Shorter OS was observed from DLBCL
patients with high miR-21 expression in the tumor tissue, while high miR-21 levels in the serum promoted
[40]
[40]
relapse free survival . Downregulated miR-199a/b also shortened progression free survival time . In
addition, CHOP or R-CHOP treated DLBCL patients with upregulated miR-200c expression displayed
[41]
shorter OS than patients with suppressed miR-200c . Induced miR-155 expression was connected with
R-CHOP resistance in DLBCL patients although miR-155 sensitized patients to AKT (protein kinase B, ak
[42]
thymoma) signaling probably by targeting p85α and SHIP1 . In contrast to that, upregulated expression
of miR-129-5p in DLBCL patients treated with CHOP or R-CHOP led to much longer median survival
[43]
than in patients with downregulated miR-129-5p . The tumor suppressor miR-146a was downregulated
in R-CHOP-treated DBCL patients who displayed drug resistance . Suppressed expression of the tumor
[44]
suppressors miR-146b-5p and miR-320d led to shorter progression free survival in CHOP-treated DLBCL
patients . Higher serum levels of miR-33a and miR-455-3p indicated better response while high levels
[45]
of miR-224 (target: CD59), miR-520d-3p and miR-1236 were connected with worse R-CHOP response in
[39]
DLBCL patients [35,46] . Suppressed miR-224 expression in the tumor tissue also indicated poor survival . In
addition, a higher R-CHOP response rate and longer survival was observed from DLBCL patients with 7q
[47]
gain, which was attributed to the upregulated expression of miR-25, miR-96, miR-182, and miR-589 . Lists
of miRNAs involved in cyclophosphamide activity in lymphoma are given in Tables 3 and 4.

MicroRNAs also seem to play a role for drug resistance in breast cancer patients receiving cyclophosphamide
[48]
as part of the TFAC therapy (paclitaxel, 5-fluorouracil, adriamycin, cyclophosphamide) . The tumor
suppressor miR-9 bound to the mRNA of human epidermal growth factor 2 (HER2) and increased the
[49]
response to cyclophosphamide . Low expression of let-7, miR-10b, miR-34, miR-155, miR-200c, miR-205,