Page 43 - Read Online

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

cancers in order to cope with alkylating drugs include elevated glutathione levels, enhanced DNA repair and
modified DNA damage signaling, as well as expression of multidrug resistance proteins such as membrane
[2]
transporters . The prodrug temozolomide is a highlight of research concerning alkylating agents because it
[3]
can penetrate the blood-brain-barrier and is clinically applied for the therapy of glioblastoma . Meanwhile,
nature has also provided very potent alkylating agents with promising anticancer activities such as
[4-6]
mitomycins, cyclopropyl-indoles, and illudins . Mitomycin C is applied for the treatment of various solid
[4]
tumors . Trabectedin is the latest natural alkylating agent that has been approved for the therapy of soft
[7]
tissue sarcoma and platinum-resistant ovarian cancer .
MicroRNAs (miRNAs) are small RNA molecules of 22-23 nucleotides and regulate numerous genes involved
[8]
in cell differentiation, cell proliferation, and cell death . Mature miRNAs usually bind to the 3’-untranslated
region of target messenger RNAs (mRNAs) and one miRNA is able to bind to various mRNAs [9-11] . MiRNAs
have become valuable tools for the diagnosis and prognosis of cancer diseases due to abnormal expression
profiles in cancers [12,13] . In addition, miRNAs regulate metastasis formation (epithelial-to-mesenchymal
transition) and survival of cancer stem-like cells [14,15] . Concerning cancer research, tumor suppressor
miRNAs and oncogenic miRNAs (oncomirs) are of particular interest and played crucial roles for the
[16]
sensitivity and resistance of various tumors to applied drugs . Prominent miRNAs with great relevance to
cancer disease are represented by the tumor suppressor let-7 family and the oncomir miR-21 [17,18] .

This review intends to give an overview of clinically approved alkylating agents and their interactions with
miRNAs in cancer diseases concerning drug activity and resistance.

SYNTHETIC ALKYLATING AGENTS AND THEIR INTERACTIONS WITH MIRNAS
Synthetic alkylating agents are widely applied for the therapy of solid tumors and of leukemia/lymphoma
diseases. Relevant synthetic alkylating agents that are dealt with in this review can be subdivided into
the following compound classes: mustards (e.g., nitrogen mustards such as mechlorethamine, melphalan,
chlorambucil, bendamustine, cyclophosphamide, estramustine), diazomethane forming prodrugs (e.g.,
dacarbazine, temozolomide), and N-nitrosoureas (e.g., BCNU/carmustine). The influence of miRNAs on the
activity of these alkylating drugs is discussed below.

NITROGEN MUSTARDS, MIRNAS AND CANCER
As mentioned above, anticancer active nitrogen mustards were developed since 1942 from highly toxic
poison gas applied or produced in both World Wars of the 20th century. In order to reduce the systemic
toxicity of nitrogen mustard poison gas and of initially applied mustard drugs like mechlorethamine, anilin
derivatives such as chlorambucil and melphalan were designed with reduced activity due to their aromatic
amine system [Figure 1]. Soon later, bendamustine and the prodrug cyclophosphamide were developed
[19]
as potent anticancer drugs [Figure 1] . In addition, the alkylating estrogen-conjugate estramustine
[19]
was disclosed [Figure 1] . Recent efforts in the field of nitrogen mustard-based anticancer research to
increase selectivity and reduce side effects included DNA-targeting strategies, brain-targeting strategies,
antibody-directed enzyme prodrug therapy and gene-directed enzyme prodrug therapy strategies, and
[19]
nitrogen mustard prodrugs activated by glutathione transferase . The alkylation mode of action of these
2-chloroethylamino derivatives includes an intramolecular reaction to an aziridium intermediate that
[19]
readily reacts with bionucleophiles . Aside cytotoxic effects on non-malignant cells, genotoxic mutagenic
effects were identified for nitrogen mustards as well.

Chlorambucil has been the standard treatment for chronic lymphocytic leukemia (CLL) for decades
and the drug is still recommended as a mainstay for the currently widely applied antibody-based
chemoimmunotherapy for CLL . Chemoresistance of CLL is often mediated by the p53-signaling pathway
[20]