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Page 4 of 13 Gambari et al. J Cancer Metastasis Treat 2019;5:55 I http://dx.doi.org/10.20517/2394-4722.2019.18

Figure 2. Scheme outlining the differences between DNA (left) and PNA (right) monomers

been demonstrated to be very efficient tools for pharmacologically-mediated alteration of gene expression,
both in vitro and in vivo [56,57] .

Summarizing, PNAs and PNA-based analogues were employed as antisense molecules targeting mRNAs,
triple-helix forming molecules targeting eukaryotic gene promoters, artificial promoters, decoy molecules
targeting transcription factors [54-56] . Relevant in the context of the present review article, PNAs have been
demonstrated to be able of altering miRNA functions, both in vitro and in vivo [58-62] . This has been recently
reviewed by Manicardi et al. .
[63]
While well-controlled studies are needed to compare the in vivo activity of PNAs to those of LNA, RNA and
other molecules exhibiting anti-sense potential, several in vivo studies on PNAs have been already reported
to sustain the usefulness of these molecules and their derivatives.

Gupta et al. tried to target miR-210 with an antisense γ-peptide nucleic acids (γPNAs), exhibiting superior
[64]
RNA-binding affinity, improved solubility, and favorable biocompatibility. The rationale for this approach
is that miR-210 is overexpressed in hypoxic cancer cells and is a key player for the adaptation of tumor
cells to hypoxia. For cellular delivery, they encapsulated the γPNAs in poly(lactic-co-glycolic acid) (PLGA)
nanoparticles. The results obtained show that γPNAs targeting miR-210 cause significant delay in growth of
a human tumor xenograft in mice compared to conventional PNAs. Furthermore, histopathological analyses
show considerable necrosis, fibrosis, and reduced cell proliferation in γPNA-treated tumors compared to
controls . In another paper, Cheng et al. efficiently inhibited the function of oncomiRNA miR-155 in a
[11]
[64]
tumor mouse model after the design and realization of a peptide-(anti-miRNA)PNA construct able to target
the tumor microenvironment and to transport the anti-miRNA PNA across the cellular plasma membranes
under the acidic conditions which characterize solid tumors. A final example is that published by Yan et
al. , demonstrating that PNA-mediated targeting of miR-21 causes inhibition of growth and migration
[65]
of breast cancer MCF-7 and MDA-MB-231 cells in vitro, and tumor growth in vivo when nude mice were
employed.

GLIOBLASTOMA
Glioblastoma multiforme (GBM), a grade IV glioma, is a lethal malignant tumor accounting for 42% of
the central nervous system tumors, the median survival being 12-15 months [66-71] . The current standard
therapeutic management of GBM is based on neurosurgery followed by chemoradiotherapy by fractionated
external-beam radiotherapy and systemic chemotherapeutic treatment with temozolomide (TMZ) and
other agents, including repurposed drugs (such as metformin, disulfiram, rapamycin and derivatives,
chloroquine, ionidamine) . There are only very limited possibilities for the treatment of subsequent
[71]
recurrences, generally with minimal clinical efficacy . Among novel therapeutic strategies for GBM, of
[69]
interest are inhibitors of aberrantly activated cell signaling pathways, including those regulated by growth
factors and their receptors, such as epidermal growth factor family and their receptors , platelet-derived
[72]
growth factors and their receptors . In addition, innovative targets for GBM experimental therapy might
[73]