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Table 7. MiRNAs with effects on the anticancer activity of estramustine phosphate
MiRNA Target Function Expression in cancers/tissues
miR-31 Apoptosis Oncomir Suppression in prostate cancer led to apoptosis
miR-4319 HER2 Tumor suppressor Suppression in prostate cancer patients led to resistance
HER2: human epidermal growth factor receptor 2

Table 8. MiRNAs with effects on the anticancer activity of dacarbazine
MiRNA Target Function Expression in cancers/tissues
miR-141 Apoptosis Tumor suppressor Expression sensitized melanoma cells
miR-200a/b/c Apoptosis Tumor suppressor Expression sensitized melanoma cells
miR-494 - Oncomir Suppression led to complete response in lymphoma patients
miR-1973 - Oncomir Suppression led to complete response in lymphoma patients

[85]
stem cells was associated with downregulation of Bax and upregulation of Bcl-2 . Downregulation of the
oncomirs miR-221/miR-222 refurnished p53 signaling pathway and promoted apoptosis of GBM cells treated
[86]
with temozolomide . MiR-141-3p is another p53-targeting oncomir leading to temozolomide resistance
[87]
in glioma cells . MAP kinase/extracellular-signal regulated kinase (ERK) signaling was induced by the
oncomir miR-299-5p, which targeted golgi phosphoprotein 3 and, thus, led to temozolomide resistance in
GBM cells . Temozolomide resistance in GBM basing on active GSK3β was overcome by upregulated miR-
[88]
[89]
101 . Further to this, miR-128 mediated temozolomide-induced cell death in glioma cells via inhibition
of mTOR signaling and suppression of insulin-like growth factor 1, phosphoinositide-3-kinase regulatory
[90]
subunit 1, rapamycin-insensitive companion of mTOR and mTOR . High expression of miR-130a
sensitized glioma cells to temozolomide via apurinic/apyrimidinic endonuclease 1 suppression and was
[91]
upregulated in GBM patients with better response to temozolomide . A direct influence on temozolomide
resistance was elucidated for miR-181d and miR-603, which suppressed the DNA repair enzyme MGMT
[92]
leading to greater sensitivity to temozolomide . In addition, miR-142-3p promoted temozolomide activity
in GBM cells by suppression of MGMT . MiR-648 and miR-767-3p were identified as further MGMT
[93]
targeting/suppressing miRNAs, which enhanced the anticancer activity of temozolomide in T98G GBM
[94]
cells . MiR-182 expression also increased temozolomide activity in GBM cells by apoptosis promotion
[95]
via c-Met, HIF2A and BCL2L12 suppression . However, expression of miR-132 caused temozolomide
[96]
resistance in GBM cells (U78MG) via downregulation of tumor suppressor candidate 3 . Temozolomide-
resistant GBM cells and tissues exhibited suppressed miR-370-3p expression levels, which is a tumor
[97]
suppressor responsible for downregulated MGMT expression and blocked DNA repair . In contrast to
that, expression of the oncomir miR-423-5p led to temozolomide resistance in glioma cells by targeting
[98]
ING-4 . Glioblastoma samples from patients treated with temozolomide revealed upregulated miR-629-
3p expression (targeting genes involved in translation and RNA processing) in case of good responders
with prolonged OS . The tumor suppressor miR-1268 also sensitized glioma cells (T98G) to temozolomide
[99]
treatment [100] . In addition, miR-1294 suppressed targeting protein for Xenopus kinesin-like protein 2 in
glioma cells leading to enhanced temozolomide activity [101] . Some miRNAs are special “Janus-type” cases
here. Although miR-181b/c are reported as tumor suppressors in GBM, reduced expression of these miRNAs
was associated with better temozolomide response [102] . And although miR-221 and miR-222 suppress MGMT,
their upregulation led to weaker responses to temozolomide [103] . In a cancer type dependent way, miR-195
acted either as a tumor suppressor (melanoma) or as an oncomir (GBM, see above). Last but not least, the
combination of temozolomide with miRNA-regulating drugs appears promising. For instance, curcumin (a
polyphenol isolated from turmeric, Curcuma longa) was able to sensitize GBM cells (C6) to temozolomide
[104]
via suppression of miR-10b . Lists of miRNAs involved in temozolomide anticancer activity are given in
Tables 9 and 10.

N -nitrosoureas, miRNAs and cancer
Anticancer active N-nitrosoureas were developed in the course of a screening program initiated by the
National Cancer Institute. Starting from the hit compound 1-methyl-3-nitro-1-nitrosoguanidine further