Journal of Oncology Pharmacy Practice - January 2022 - 155

Mehdizadeh et al.
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cells treated with this molecule showed inhibition of AKT
activity as a result of reduced Ser 473 phosphorylation.
The molecular docking analysis showed that this molecule
binds to the ligand-binding domain of AKT.62 The
2,4-dihydroxy-30-methoxy-40-ethoxychalcon (DMEC) is
a compound extracted from the plant Caragana pruinosa
that reduces AKT phosphorylation. Treatment of
RPMI-8226, MM.1S, and U266 cells with different concentrations
of this herbal extract increased the expression
of C3, C9, Bad, Cyto C and decreased the expression
levels of Bcl-2 and PARP.63
Triptolide (TPL) is an herbal component that is extracted
from the Tripterygium wilfordii Hook. It is reported that
TPL induces apoptosis in the dexamethasone-resistant
myeloma cells by reducing AKT phosphorylation. Yang
et al.64 showed that TPL increased the toxic activity of
bortezomib/PS-341 against different MM cell lines. The
6-O-angeloylplenolin is also a herbal component that
target AKT. It is an effective molecule to suppress proliferation
of dexamethasone-resistant MM cell lines. The
6-O-angeloylplenolin is also able to increase the efficacy
of bortezomib on MM cell lines.65
Silybin is a compound derived from the Silybum
marianum, whose anti-cancer properties have been proven
in various cancers. According to the study by Feng et al.66,
silybin significantly downregulated the expression of PI3K,
p-Akt, and p-mTOR in U266 cells and prevented cell proliferation
in these cells. In another study, the plumbagin
suppressed the proliferation of OPM1 cells through downregulation
of PI3K, p-Akt, and p-mTOR.67
Polydatin with the formula 3,4,5′-trihydroxystibene3-monoglucoside
is the glycoside form of resveratrol,
which is a well-known herbal molecule in traditional
Chinese medicine. Polydatin increased autophagy and
apoptosis in RPMI-8226 cells by targeting and inhibiting
the phosphorylation of mTOR and p70s6k.68
Noncoding RNAs
The gene expression regulation is a highly complex
biological process which occurs in a coordinated manner
via several mediators such as microRNAs (miRNAs).
This biological process profoundly regulates cell proliferation,
differentiation, growth, and apoptosis.79,80 miRNAs
are a group of noncoding RNAs with 21 to 25 nt length.
These molecules attach to their complementary mRNA in
the cytoplasm and lead them to the RISC complex, where
their targets will be destroyed.81 Due to the important role
of miRNAs in regulating gene expression, any unbalanced
expression of these molecules may cause various diseases,
including cancers. On the other hand, due to the fact that the
over and downregulation ofmiRNAs are highly observed in
various cancers, restoring their expression balance provides
a powerful therapeutic tool for the treatment of various
malignancies. It is found that the unbalanced expression
of some miRNAs is responsible for dysregulation of PI3K
signaling pathway mediators in MM. For example, overexpression
of miR-20a has been frequently reported in
patients with MM. Jiang et al.69 revealed that suppressing
miR-20a expression reduced proliferation, migration, and
colonization of MM cell lines via the PTEN/PI3K/AKT
pathway.
miR-342/miR-363 indirectly downregulate the expression
ofAKT. Gowda et al. reported that these miRNAs alter AKT
expression by targeting RUNX-2 transcription factor. They
found an adverse relationship between miR-342/miR-363
and RUNX-2 expressions in MM patients. It seems that
forced expression of miR-342/miR-363 can be a therapeutic
strategy for treatment of MM through downregulation of
RUNX-2 and consequently AKT.70
Although the role of miRNA in cancer development has
become more prominent in recent years, our knowledge
regarding the expression pattern of these molecules is still
incomplete. Future studies pave the way for the design of
new treatment strategies by introducing more miRNAs targeting
PI3K mediators.
Future perspective
Despite all advances in cancer therapy, there are still serious
challenges in treatment of some cancer types due to the lack
of an effective drug regimen to overcome drug resistance.
In the meantime, finding new drugs and treatment strategies
can be helpful. By illuminating the dark side of cellular signaling
pathways and their function on cell hemostasis, one
can hope to build and design new drugs that target the mediators
involved in these biological pathways. On the other
hand, with the advancement of computer science and biological
software, it is possible to design new small molecules
and evaluate their binding to the target molecules.
This could be promising for the design of new drugs in
the treatment of MM.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research,
authorship and/or publication of this article.
ORCID iD
Behrouz Farhadihosseinabadi
6332-3067
References
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https://orcid.org/0000-0001
https://www.orcid.org/0000-0001 https://www.doi.org/10.3390/ph13110396
Journal of Oncology Pharmacy Practice - January 2022

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