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Biersack. Cancer Drug Resist 2019;2:1-17 I http://dx.doi.org/10.20517/cdr.2019.09 Page 11

Figure 4. Structures of the natural alkylating agents mitomycin C and trabectedin

Table 11. MiRNAs with effects on the anticancer activity of BCNU
MiRNA Target Function Expression in cancers/tissues
let-7b - Tumor suppressor Dysregulated in glioma cells upon BCNU treatment
miR-21 Spry2 Oncomir Expression in glioma cells induced resistance
miR-125b-2 - Oncomir Dysregulated in glioma cells upon BCNU treatment
miR-133-1 - Oncomir/tumor suppressor Dysregulated in glioma cells upon BCNU treatment
miR-181d - Oncomir Suppression led to prolonged survival of GBM patients
miR-183 - Oncomir Dysregulated in glioma cells upon BCNU treatment
miR-221 PTEN Oncomir High expression in GBM induced resistance
PTEN: phosphatase and TENsin homolog; Spry2: sprouty homolog 2

[127]
transfected with miR-1915 mimics revealed enhanced mitomycin C sensitivity by suppression of Bcl-2 . A
list of miRNAs involved in mitomycin C anticancer activity is given in Table 12.

Since mitomycin C is a DNA-damaging drug, its long-term genotoxic effects and the inheritable aberration
of miRNA expression induced by mitomycin C were investigated. Indeed, the treatment of HeLa cells with
mitomycin C exhibited upregulated inherited expression of oncomirs such as miR-19b-3p, miR-21-3p, miR-
30a-3p, miR-30e-3p, and miR-182-5p as well as suppressed inherited expression of the tumor suppressors
miR-23b-3p, miR-29b-3p, miR-99a-5p, miR-99b-5p, miR-100-5p, miR-148a-3p, miR-193a-3p, ,iR-340-5p, and
[128]
miR-365-3p . It is possible that new tumors can form basing on the long-term effects of mitomycin C and
the observed aberrant miRNA expression.

TRABECTEDIN, MIRNAS AND CANCER
Trabectedin (ecteinascidin 743, Yondelis®) is a rather new natural alkylating agent that belongs to the class
of tetrahydroisoquinoline alkaloids. It was isolated from the Caribbean tunicate Ecteinascidia turbinata,
which is only the host of the trabectedin-producing symbiont Endoecteinascidia frumentensis [129] . The high
anticancer activity of trabectedin led to its clinical approval for the treatment of soft tissue sarcoma [129] . The
unique DNA-damaging mechanism of trabectedin includes binding to nitrogen-N2 of guanine DNA bases
in the minor groove. This DNA-trabectedin adduct interacts with DNA repair proteins of the transcription-
coupled nucleotide excision repair DNA-repair system which causes cell death via the formation of double-
strand breaks mainly in homologous recombination-deficient cells [129] . This mechanism is almost unique
among known alkylating agents and only illudins have revealed a similar mode of action [130] . Trabectedin
also blocked the transcriptional activity of fused in sarcoma-C/EBP-homologous protein (FUS-CHOP) [131] .
The difference in miRNA expression between trabectedin-sensitive and trabectedin-resistant myxoid
liposarcoma cells (402-91 sensitive and 402-91/ET trabectedin-resistant cells) was investigated and the
resistant cells showed two-fold higher miR-21 expression (target: PDCD4/programmed cell death 4) as well