Page 102 - ITPS-7-1

INNOSC Theranostics and
Pharmacological Sciences Plants immunoactivity: In silico study

et al., 2009). The release of inflammatory modulators is (DEPTOR) has been identified as an effective inhibitor
regulated by multiple signaling pathways, one of which of both mTORC1 and mTORC2 . Increased expression
[51]
is mitogen-activated protein kinase (MAPK) pathway. of DEPTOR inhibited mTORC1, relieving the feedback
MAPK is responsible for multiple cellular processes, inhibition of ribosomal protein S6 kinase. Consequently,
including cell survival, inflammation, stress response, and this results in the activation of AKT and the survival of
cell proliferation (Moens, Kostenko and Sveinbjørnsson, multiple myeloma cells.
2013). Numerous pathways interact with the PI3K/AKT/

Myeloid differentiation factor 88 (MyD88), TRIF, and mTOR pathway, in addition to the feedback loops within
other adaptor proteins bind to TLRs, inciting the activation it. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK
of NF-κB and the consequent production of inflammatory pathways exhibit the most intricate and well-documented
cytokines . This cascade triggers the expression of interaction. Yu et al. further discovered that suppressing
[45]
proinflammatory cytokines, chemokines, inducible ERK using the MEK inhibitor U0126 enhances the
enzymes such as cyclooxygenase (COX)-2 and inducible binding of Grb2-associated binder-1 (Gab1) with PI3K,
[52]
nitric oxide synthase (iNOS), growth factors, immune consequently activating the PI3K/AKT pathway . A more
receptors, and adhesion molecules such as intercellular cell recent study has demonstrated the successful treatment of
adhesion molecule 1 (ICAM-1) and vascular cell adhesion metastatic and primary colorectal cancers by inhibiting
molecule 1 (VCAM-1) due to NF-κB activation . the PI3K/mTOR pathways. This highlights the pathway’s
[46]
The STAT protein family constitutes a potent force in potential as a promising route for addressing these lethal
[53]
immunoregulation. Several proteins, including JAK, cancers .
GATA3 (a transcription factor that controls Th2 cytokine In addition to cell differentiation, proliferation, and
production), and RAR-related orphan receptor gamma survival, the MAPK pathway is an evolutionarily conserved
(RORt-Th17 transcription factor), are involved in this cell regulatory signaling network. Inflammatory cytokines
process, as elucidated by O’Shea et al. . Different STAT such as TNF-a, IL-6, and IGF1 activate this pathway,
[47]
proteins also affect the levels of cytokines. Meanwhile, triggering subsequent kinase cascades, namely RAS, RAF,
recent studies underscore the pivotal roles of STAT3 in MEK, and MAPK, resulting in altered gene expression.
tumor cell growth and proliferation, recommending it as The MAPK pathway harbors two main oncogenes,
a therapeutic target for inflammation-related diseases and NRAS and KRAS, which are frequently aberrant in many
tumor management . malignancies. Notably, these genes are often affected in
[48]
multiple myeloma, with a cumulative incidence of 20
The PI3K-Akt/mTOR pathway, which is targeted for [54]
anti-multiple myeloma treatment, has been identified as – 35% . RAS mutations are thought to be progressive
events, as they are uncommon in the initial phases of
a hub. However, activating mutations in PI3K and AKT multiple myeloma but become more common in later
have not been detected in multiple myeloma patients . disease progression .
[49]
[55]
At the same time, a small percentage of multiple myeloma
patients experience a deficiency in the phosphatase and In terms of compounds, researchers have identified
tensin homolog (PTEN) . Despite this, the pathway plays more than ten active phytochemical constituents.
[50]
a crucial role in the survival and proliferation of multiple Withaferin A, for instance, has been shown to suppress
myeloma cells. Elevated IL6 secretion by stromal cells, TNF-induced NF-B activation in human myeloid leukemia
[56]
along with the elevated secretion of vascular endothelial KBM-5 cells . In both in vitro and in vivo studies, sitosterol
growth factor (VEGF) and insulin-like growth factor and kaempferol have also demonstrated hematological and
[57]
(IGF) by multiple myeloma cells due to multiple myeloma immunomodulatory effects . In a kidney cancer cell line,
interactions, contribute to the pathway’s activation. These withaferin-A induced dose-dependent apoptotic cell death
cytokines activate their corresponding binding sites on and PARP cleavage through the downregulation of the
[58]
multiple myeloma cells, promoting tumorigenesis by STAT-3 pathway .
upregulating signaling events such as the PI3K/AKT/ GO enrichment analysis demonstrated that the targets
mTOR, mitogen-activated protein kinase/extracellular of the active compounds in W. somnifera and A. barbadensis
signal-regulated kinase (MEK/ERK), and Janus kinase/ were involved in diverse immunomodulatory associated-
signal transducer and activator of transcription (JAK/ molecular functions. Notably, the protein kinase activity is
STAT) pathways. The complexity of the PI3K/AKT/mTOR the most significantly enriched molecular function of the
pathway is amplified by the presence of multiple feedback bioactive-multiple myeloma’s immune gene target, which
loops and interactions with various other pathways. holds unique therapeutic potential in the treatment of
DEP domain-containing mTOR interacting protein multiple myeloma . In the realm of multiple myeloma
[59]

Volume 7 Issue 1 (2024) 13 https://doi.org/10.36922/itps.1076