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Biersack. Cancer Drug Resist 2019;2:1-17 I http://dx.doi.org/10.20517/cdr.2019.09 Page 9

Table 9. Tumor suppressing miRNAs with effects on the anticancer activity of temozolomide
MiRNA Target(s) Expression in cancers/tissues
miR-16 Bcl-2 Suppression in GBM led to resistance
miR-29c MGMT, REV3L Suppression in glioma led to resistance
miR-30a Beclin 1 High expression sensitized glioma cells
miR-101 GSK3β High expression sensitized GBMs
miR-128 IGF1, PIK3R1, RICTOR, mTOR Expression sensitized glioma cells
miR-130a APE1 High expression sensitized glioma cells
miR-136 AEG-1 High expression sensitized glioma cells
miR-142-3p MGMT Expression sensitized GBM
miR-143 N-RAS High expression sensitized GBM
miR-181d MGMT Expression sensitized GBM
miR-182 c-MET, HIF2A, BCL2L12 High expression sensitized GBM
miR-195 PHB1 Expression sensitized melanoma
miR-370-3p MGMT Suppression in resistant GBM
miR-603 MGMT High expression sensitized GBM
miR-629-3p Translation High expression in GBM prolonged OS
miR-1268 Expression sensitized glioma cells
miR-1294 TPX2 Expression sensitized glioma cells
AEG-1: astrocyte elevated gene-1; APE1: apurinic/apyrimidinic endonuclease 1; Bcl-2: B-cell lymphoma 2; GSK3β: glycogen synthase kinase
3β; IGF1: insulin-like growth factor 1; MGMT: O6-methylguanine-DNA methyltransferase; mTOR: mammalian target of rapamycin; N-RAS:
neuroblastoma rat sarcoma oncogene; PHB1: prohibitin 1; PIK3R1: phosphoinositide-3-kinase regulatory subunit 1; REV3L: reversionless
3-like; RICTOR: rapamycin-insensitive companion of mTOR; TPX2: targeting protein for Xenopus kinesin-like protein 2

analogs were prepared leading to 1-methyl-1-nitrosourea which was active against intracerebrally implanted
murine leukemia [105] . Further fine-tuning of this compound finally led to carmustine/BCNU (bis-
chloroethylnitrosourea, Figure 3) which entered clinical trials in 1964 and was approved by the FDA in
1977 for the treatment of brain tumors (BCNU passes the blood-brain-barrier because of its lipophilicity),
lymphomas and myeloma [106] . A newer study recommends the application of BCNU for the treatment of
recurrent GBM [107] . BCNU is a prodrug, which decomposes to afford alkylating chloroethyl moieties that
can form DNA interstrand crosslinks [108] . Carbamoylation of nucleoprotein lysine residues via isocyanate
[109]
intermediates can also play a role for the anticancer mode of action of BCNU .

Expression analysis of BCNU-treated glioma cells led to dysregulation of let-7b (tumor suppressor), miR-
125b-2 (oncomir), miR-133a-1 (tumor suppressor/oncomir), and miR-183 (oncomir) [110] . It was also shown
that miR-21 expression induced BCNU-resistance in glioma cells via downregulation of Spry2 (sprout
homolog 2) [111] . Although miR-181d was identified as a tumor suppressor and temozolomide-sensitizing
factor (see above), GBM patients with implanted BCNU wafers displayed prolonged overall and progression-
free survival in case of suppressed miR-181d expression [112] . In addition, high expression of the oncomir
miR-221 suppressed PTEN and led to PI3K/Akt activation and resistance to BCNU [113] . A list of miRNAs
involved in BCNU anticancer activity is given in Table 11.

NATURAL ALKYLATING AGENTS AND THEIR INTERACTIONS WITH MIRNAS
Natural alkylating agents were investigated for anticancer activity since the 1950’s [114,115] . Meanwhile, natural
alkylating agents are widely applied for the therapy of various cancer diseases. The alkaloids mitomycin C
and trabectedin were approved for the therapy of cancer [Figure 4]. The influence of miRNAs on the activity
of these natural alkylating drugs is discussed below.

MITOMYCINS, MIRNAS AND CANCER
Mitomycins are bacterial indole alkaloids. The first mitomycins A and B were isolated in 1956 before
mitomycin C was obtained as blue-violet crystals from Streptomyces caespitosus by Japanese groups in
1958 [116,117] . Mitomycin C turned out to be the most anticancer active derivative of this group of mitomycins