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Figure 3. Structure of the N-nitrosourea alkylating drug carmustine/BCNU

Table 10. Oncomirs with effects on the anticancer activity of temozolomide
MiRNA Target(s) Expression in cancers/tissues
miR-9 PTCH1 High expression in resistant GBM
miR-10* - High expression in resistant GBM
miR-10b - Suppression sensitized GBM cells
miR-17 ATG7 Suppression sensitized GBM cells
miR-21 Bax/Bcl2 Suppression sensitized GBM cells
miR-93 p21 Expression correlated with resistance in glioma cells
miR-125b-2 Bax Expression correlated with glioblastoma stem cell resistance
miR-132 TUSC3 Expression correlated with resistance in GBM cells
miR-138 BIM High expression in resistant GBM
miR-141-3p p53 Expression correlated with resistance in glioma cells
miR-195 - High expression in resistant GBM
miR-221 p53 Suppression promotes apoptosis in GBM cells
miR-222 p53 Suppression promotes apoptosis in GBM cells
miR-299-5p GOLPH3 Expression correlated with resistance in GBM cells
miR-423-5p ING-4 Expression correlated with resistance in glioma cells
miR-455-3p SMAD2 High expression in resistant GBM

ATG7: autophagy-related protein 7; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; BIM: BCL-2-interacting mediator of cell
death; GOLPH3: golgi phosphoprotein 3; ING-4: inhibitor of growth protein 4; PTCH1: patched homolog 1; SMAD2: mothers against
decapentaplegic homolog 2; TUSC3: tumor suppressor candidate 3

and entered clinical trials in Japan shortly after its discovery [118] . Currently, it is applied for the treatment of
localized bladder cancer, anal cancer, head-and-neck cancer, and breast cancer (palliative 2nd or 3rd line
[119]
treatment) . Mitomycin C is a prodrug and activated mitomycin C forms DNA crosslinks that are highly
lethal to cancer cells [120] . Activation of mitomycin C occurs via reduction of the benzoquinone scaffold
to a hydroquinone (a reaction catalyzed by enzymes such as DT-diaphorase). Subsequent elimination of
methanol forms a reactive aziridine system, which reacts with DNA via aziridine ring opening. Elimination
of carbamate enables a second alkylating step leading to DNA crosslinking [120] .

Transfection of HT-29 colon cancer cells with let-7-1 suppressed COP9 signalosome expression and increased
mitomycin C activity . Expression of the tumor suppressor miR-31 enhanced the tumor growth inhibition
[121]
[122]
of urothelial bladder cancer by mitomycin C both in vitro and in vivo . MiR-31 inhibited integrin α5 directly
[122]
and suppressed Akt and ERK signaling . In addition, miR-34a expression sensitized medulloblastoma to
[123]
mitomycin C treatment by downregulation of melanoma antigen A and upregulation of p53 . In contrast
to that, inhibition of miR-191-5p expression led to higher mitomycin C activity against breast cancer cells
[124]
via induction of apoptosis, SRY-box 4, and p53 . A slight increase in mitomycin C resistance was observed
for Snail-expressing mesenchymal MCF-7 breast cancer cells, which displayed suppressed miR-200 family
expression [125] . Mitomycin C was shown to induce senescence in human mesenchymal stem cells via
upregulation of the tumor suppressor aminoacyl-tRNA synthetase-interacting multifunctional protein 3/
[126]
p18, and suppression of AIMP3/p18 was observed for miR-543 and miR-590-3p . This mechanism may also
play a role for the anticancer activity of mitomycin C. Oxaliplatin-resistant HCT-116/l-OHP colon cancer cells