Page 132 - EJMO-9-2

Eurasian Journal of Medicine and
Oncology
Anticancer effects of phytocomposites

transferase, is essential for HRAS membrane localization and inhibiting RAS activation and stopping cell growth and cancer
protein-protein interactions. Palmitoylation, a lipid post- cell proliferation. In addition, tecomaquinone I exhibits
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translational change, occurs when the palmitoyl chain is joined strong anti-inflammatory, antioxidant, and anti-microbial
to the cysteine group. It aids in maintaining the activity, effects. It has been identified as a potent natural inhibitor of
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stability, and trafficking of proteins while facilitating protein human farnesyl transferase (IC 0.065 ± 0.004 µM). 53
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clustering and mediating the affinity of a protein for a lipid Cytokines are essential for controlling the response
raft. Palmitoylation is catalyzed by palmitoyl transferases. of the host immune system to infections but can also
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Ubiquitination is the ubiquitin-conjugating system responsible contribute to cancer development. They activate signaling
for the post-translational alteration of proteins. This process pathways through the Janus kinase (JAK) and signal
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promotes protein breakdown by controlling proteasome transducer and activator of transcription (STAT) pathways
activity, which is catalyzed by the conserved E1-E2-E3 three- by binding to receptors and activating responses. The
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enzyme cascade in an adenosine triphosphate (ATP)-dependent JAK-STAT pathway is essential for cellular proliferation and
manner. 45,46 differentiation. On cytokine binding to receptors, JAKs are
Farnesylation is a crucial step for HRAS to mature into activated, leading to the transfer of phosphate from ATP
an active state. When HRAS remains in an active state to the tyrosine residues of receptors. Subsequently, JAKs
for an extended period, it becomes mutated. Given that phosphorylate STATs, which become activated, migrate
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HRAS proteins play a crucial role in the cell cycle, which into the nucleus, and modify gene expression. This shows
regulates cell proliferation and apoptosis, alterations the significance of JAKs and the need for JAK inhibitors in
in these proteins can suppress cell cycle arrest, thereby cancer treatment, as they can slow the spread of cancerous
stimulating the growth of tumor cells. 48 tissue. The JAK-STAT pathway undergoes various changes
Farnesyl transferase inhibitors are a class of signal- in solid tumors, including head and neck malignancies,
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transducing inhibitors designed to target the post- lung cancers, breast cancers, and prostate cancers.
translational modifications of HRAS. These inhibitors A protein kinase inhibitor like abemaciclib can
prevent proteins from mislocalizing to cellular inhibit cancer cell development. JAK inhibitors, such
compartments due to their inability to localize on the cell as ruxolitinib, inhibit JAK proteins. Ruxolitinib, when
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membrane. Consequently, oncogenic activity is suppressed combined with cisplatin has been shown to reduce STAT3
by interfering with downstream signaling pathways, which activation and cell proliferation, promote apoptosis, and
rely on the appropriate localization and interaction of suppress tumor growth in preclinical in vitro and in vivo
the proteins on the membrane. Mislocalized proteins models of cisplatin-resistant NSCLC with elevated JAK2
accumulate in intracellular compartments, activating and STAT3 activation levels. The p38α mitogen-activated
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cellular stress and inducing apoptosis in cancer cells. protein kinase inhibitor is a potential therapeutic agent
Thus, preventing farnesylation using a farnesyl transferase for oral cancer. It inhibits p38 activation – a pathway that
inhibitor is important for the proper function and promotes cellular proliferation, migration, and invasion.
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localization of proteins. 49 In addition, PKC412, an oral protein kinase inhibitor,
Farnesyl transferase inhibitors have demonstrated inhibits the cell cycle and exhibits anti-angiogenic
significant cytotoxic effects in various studies. For properties. 60
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instance, the farnesyl transferase inhibitor SCH66336 Brevilin A, a natural JAK inhibitor, suppresses the
(lonafarnib) has shown antitumor activities in head and STAT3 pathway by inhibiting STAT3 signaling and
neck squamous cell carcinoma (HNSCC) both in vitro inhibiting STAT3-dependent cell proliferation. It
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and in vivo. Its antitumor activity is mediated by insulin- demonstrates high selectivity for STAT signaling pathway-
like growth factor binding protein-3, which inhibits dependent JAK activity without affecting other signaling
angiogenesis. Tipifarnib, the first farnesyl transferase pathways. Brevilin A also reduces STAT1 phosphorylation
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inhibitor to enter clinical development in 1997, has been and its target gene, IRF1, and inhibits the JAK tyrosine
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shown to inhibit the growth of MCF-7 xenografts and kinase domain JH1. Moreover, brevilin A has been shown
induce cell death by increasing the expression of the cell to induce apoptosis and suppress STAT3 activation in
cycle inhibitory protein, p21. Moreover, combining human lung cancer cells. 63
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tipifarnib and tamoxifen significantly increased tumor For cancer cells to survive, migrate, and metastasize, the
regression in endocrine therapies. 5 extracellular matrix (ECM) must be properly controlled, as
Tecomaquinone I, a naturally occurring naphthoquinone, aberrant ECM adhesion can lead to cancer cell invasion
acts as a farnesyl transferase inhibitor. It prevents the and metastasis. The focal adhesion kinase (FAK)-
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farnesylation of target proteins, including RAS, thereby mediated phosphorylation of Src and the direct interaction

Volume 9 Issue 2 (2025) 124 doi: 10.36922/ejmo.7073