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Biersack. Cancer Drug Resist 2019;2:1-17 I http://dx.doi.org/10.20517/cdr.2019.09 Page 7

Figure 2. Structures of the alkylating agents dacarbazine and temozolomide

Table 6. MiRNAs with effects on the activity of cyclophosphamide in miscellaneous cancers
MiRNA Target Function Expression in cancers/tissues
miR-27b CYP3A4, VDR Oncomir Overexpression in resistant pancreas cancer cells
miR-298 CYP3A4, VDR Oncomir Overexpression in resistant pancreas cancer cells
miR-575 Invasion Oncomir Suppression led to sensitive lung cancer cells
miR-589 EMT Tumor suppressor High expression led to sensitive lung cancer cells

CYP3A4: cytochrome P3A4; EMT: epithelial-to-mesenchymal transition; VDR: vitamin D receptor

Growth inhibition of melanoma cells by dacarbazine was mediated by induction of the expression of miR-
[64]
200 family miRNAs (miR-141, miR-200a/b/c) which regulate apoptosis . Dacarbazine is also widely
applied for the treatment of lymphomas as part of the ABVD therapy (adriamycin, bleomycin, vinblastine,
dacarbazine). Complete response to ABVD therapy was achieved by classical Hodgkin lymphoma patients
[65]
with reduced miR-494 and miR-1973 plasma levels . A list of miRNAs involved in dacarbazine activity in
various cancers is given in Table 8.

The development of temozolomide as an anticancer drug started in the 1980’s and is a nice example of the
[63]
productive interplay between chemists, pharmacists and clinicians during the development process .
Temozolomide is a prodrug and decomposes in aqueous solution. Initially CO is released from the
2
[63]
molecule whereupon diazomethane is formed that reacts with bionucleophiles . The interplay between
temozolomide and miRNAs in cancer was thoroughly studied over the last years. Initial studies revealed that
temozolomide-induced apoptosis was inhibited by upregulated miR-21 accompanied by decreased Bax/Bcl-
2 ratio and caspase-3 activity in GBM cells [66,67] . Treatment of GBM cells with temozolomide led to increased
miR-21 expression and GBM cells were sensitized to temozolomide by downregulation of miR-21 and
miR-17 [68-70] . In particular, antisense miR-21 formulated with PLGA [poly(lactic-co-glycolic acid)]
[71]
nanoparticle carriers increased the anticancer activity of temozolomide against GBM cells . Temozolomide-
resistant GBM cells also exhibited increased miR-10a*, miR-195 (also in cancer stem cells of GMB tumors
via mothers against decapentaplegic homolog 2 targeting), and miR-455-3p expression [72,73] . However, in
[74]
melanoma cells, miR-195 functioned as a tumor suppressor by suppression of prohibitin 1 . In addition,
chemoresistance to temozolomide was associated with upregulation of miR-9 (targeting/patched homolog
1) in CD133-positive GBM cells and of Bcl-2-interacting mediator of cell death - targeting miR-138 [75-77] .
Downregulation of the tumor suppressor miR-16 increased Bcl-2 activity and led to temozolomide resistance
[78]
in glioma cells . Suppressed miR-29c expression associated with upregulated reversionless 3-like (REV3L)
[79]
led to temozolomide resistance in glioma cells . In addition, miR-29c enhanced temozolomide activity by
[80]
indirect suppression of MGMT . MiR-30a expression also enhanced temozolomide activity against U251
[81]
GBM cells by inhibition of autophagy and suppression of beclin 1 . Upregulation of the tumor suppressor
miR-136 led to higher temozolomide activity in glioma cells by suppression of astrocyte elevated gene 1
[82]
(AEG-1) . Similarly, induced miR-143 expression increased temozolomide activity against GBM cells via
[83]
neuroblastoma rat sarcoma oncogene targeting . The oncomir miR-93 led to temozolomide resistance
[84]
of glioma cells by upregulation of p21 . MiR-125b-2 induced temozolomide resistance in glioblastoma