Page 133 - EJMO-9-2

Eurasian Journal of Medicine and
Oncology
Anticancer effects of phytocomposites

of integrins with Src through the cytoplasmic domain play markers, including vascular endothelial growth factor
key roles in the adherence of cancer cells to the ECM. 64,65 (VEGF) and cyclooxygenase-2, and blocks key signaling
Src, a member of the membrane-bound non-receptor pathways Wnt/β-catenin, mTOR, NF-κB, PI3K/Akt, JAK-
tyrosine kinase family, is frequently expressed in various STAT, and others in different cancer cells. These findings
malignancies and acts as a key mediator. Specifically, contribute to elucidating the anticancer mechanism of
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Src activates the Akt-mediated pro-survival pathway, evodiamine. In human lung cancer cells, A549 and
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rendering cells resistant to anoikis, a form of detachment- H1299, evodiamine was found to substantially enhance
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induced cell death. In addition, Src facilitates cell motility mitochondrial membrane depolarization, increase the
by activating Rac and cell division control protein 42 cell death rate, and marginally decrease the Bcl-2/Bax
homolog, leading to cytoskeletal reorganization. These ratio. In addition, it accelerated the mitochondrial release
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alterations collectively enable cancer cells to acquire pro- of cytochrome C into the cytoplasm, activating a series
metastatic characteristics. Src kinases are also involved in of pro-apoptotic pathways, including caspases 3 and 9.
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invadopodia formation through the phosphorylation of Evodiamine also inhibited the PI3K/Akt and MAPK/
cortactin and other targets, regulating invadopodium ERK signaling pathways in human pancreatic cancer
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maturation by activating the Abl-related non-receptor cells, Panc-1 and SW1990, as well as the phosphorylation
tyrosine kinase Arg. Constitutively active Src kinase can of transcriptional activator 3 and signal transduction to
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enhance invadopodia formation, which is crucial for inhibit autophagy. Furthermore, evodiamine exhibits
tumor invasion. Invadopodia are actin-rich structures that anti-metastatic properties by blocking cancer cell
facilitate the formation of invasive cytoplasmic extensions, migration and invasion. This is achieved by regulating
allowing cancer cells to breach the endothelium and the expression and activity of matrix metalloproteinases,
project into the adjacent environment, leading to cancer which are essential for ECM degradation and tumor cell
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cell extravasation. Src kinases have been seen as a desirable invasion. Metastasis, the spread of cancer to distant
target for cancer treatment. Given their role in cancer organs, remains a significant challenge in cancer treatment.
progression, Src kinases are considered desirable targets Evodiamine’s strong anti-angiogenic impact is crucial, as it
for cancer treatment. Src inhibitors impede tumor cell involves inhibiting the growth of new blood vessels that
migration and invadopodia development. Dasatinib, supply oxygen and nutrition to tumors. By disrupting this
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the first Src inhibitor authorized by the FDA, is used to supply, tumor growth and metastasis can be halted. The
treat acute lymphoblastic leukemia with the Philadelphia anti-angiogenic properties of evodiamine are primarily
chromosome and has shown anti-proliferative, anti- due to its ability to target angiogenic factors and signaling
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invasive, anti-angiogenic properties in solid tumors. pathways, including VEGF and NF-κB. In OSCC, high
Bosutinib has demonstrated a positive effect in patients mobility group box-1 (HMGB1) or receptor for advanced
with locally progressed or metastatic breast cancer by glycation end products (RAGE) is responsible for the
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extending the time to progression. Despite the efficacy invasive behavior of cancer cells. Silencing RAGE has been
of bosutinib, the clinical development of commercial Src shown to suppress the proliferation of HSC-4 cells. Notably,
inhibitors has been halted due to side effects. 72,73 Saracatinib evodiamine demonstrates remarkable antitumor effects by
is another Src inhibitor approved by the FDA, while PP2, directly binding to HMGB1 and reducing the activity of
an Src inhibitor, has been shown to inhibit the cell growth the RAGE pathway by affecting the interaction between
and progression of HNSCC by regulating the epithelial- HMGB1 and RAGE. By targeting RAGE, evodiamine
mesenchymal transition pathway. 74 significantly inhibited the proliferation, invasion, and
angiogenesis of OSCC cells by affecting the AGE/RAGE
Erybraedin A is a natural Src inhibitor that prevents 81
the activation of the signals related to cell-ECM adhesion, signal transduction system. In addition, evodiamine has
been found to inhibit tumor growth and the expression of
thereby controlling cancer progression. It inhibits the glutamyl-prolyl tRNA synthetase (EPRS), highly expressed
activation of Src, FAK, and Akt, which downstream targets. in OSCC, in a xenograft model. It also impacts cell
Erybraedin A suppresses NSCLC cell viability, clonogenic proliferation, glutamine metabolism, and EPRS expression
survival, and tumorigenicity by inducing apoptosis. in Cal27 and SAS cell lines. A nanocomposite system
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In addition, it inhibits cell adhesion to fibronectin by comprising folic acid-modified graphene quantum dots
inactivating Src in NSCLC. loaded with evodiamine showed a high growth inhibitory
The alkaloid evodiamine has been shown to modulate rate of OSCC cells, exceeding 50% (P < 0.01). In a xenograft
the activity of various molecular targets, including kinases, model using tumor-bearing nude mice, graphene quantum
transcription factors, and multiple signaling pathways. It dots functionalized with folic acid loaded with 10%
significantly downregulates the expression of several tumor evodiamine significantly reduced tumor volume by 19%. 83

Volume 9 Issue 2 (2025) 125 doi: 10.36922/ejmo.7073