Exploiting new strategies in combating head and neck carcinoma: A comprehensive review on phytochemical approaches passing through PI3K/Akt/mTOR signaling pathway.

Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross-linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti-inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC.

2-methylpyridine-1-ium-1-sulfonate modifies tumor-derived exosome mediated macrophage polarization: Relevance to the tumor microenvironment.

The compound "2-methylpyridine-1-ium-1-sulfonate" (MPS) is the active constituent of Allium hirtifolium Boiss. bulbs with potent anti-angiogenic and anti-cancer activities. Tumor microenvironment (TME) plays a key role in tumor progression via tumor derived exosome (TEX) mediated polarization of M2 type tumor associated macrophages (TAMs). In this study, we explored direct and colorectal cancer (CRC) exosome-mediated impacts of MPS on macrophage polarization to find out whether MPS could modify TEX in favor of anti-tumor M1-like macrophage polarization. After MPS isolation and characterization, first its direct anti-cancer effects were evaluated on HT-29 cells. Then, TEX were isolated from untreated (C-TEX) and MPS-treated (MPS-TEX) HT-29 cells. THP-1 M0 macrophages were incubated with MPS, C-TEX and MPS-TEX. Macrophage polarization was evaluated by flow cytometry, ELISA and gene expression analysis of several M1- and M2-related markers. MPS induced apoptosis and cell cycle arrest and reduced the migration ability of HT-29 cells. C-TEX polarized M0 macrophages toward a mixed M1-/M2-like phenotype with a high predominance of M2-like cells. Macrophage treatment with MPS was associated with the induction of M1-like phenotype. Also, MPS was demonstrated to ameliorate TEX-mediated effects in favor of M1-like polarization. In conclusion, our study addresses for the first time, the potential capability of MPS in skewing macrophages toward an anti-cancer M1-like phenotype both directly and in a TEX-dependent manner. Thus, in addition to its direct anti-cancer effects, this compound could also modify TME in favor of tumor eradication via its direct and TEX-mediated effects on macrophage polarization as a novel anti-cancer mechanism.

Association of Vitamin D Receptor Polymorphisms (FokI (Rs2228570), ApaI (Rs7975232), BsmI (Rs1544410), and TaqI (Rs731236)) with Gastric Cancer in a Kurdish Population from West of Iran.

BACKGROUND: The association of 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) and its receptor, vitamin D receptor (VDR), with cancer types have been studied. However, there are controversial findings regarding the association of specific VDR polymorphisms with different kinds of cancers. In the current study, we investigated the association of VDR polymorphisms (Fok1 (rs2228570), ApaI (rs7975232), BsmI (rs1544410), and TaqI (rs731236)) with the risk of gastric cancer in a Kurdish population of Kermanshah in Iran for the first time. METHODS: In this case-control study, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used in 99 gastric cancer patients and 100 healthy subjects as controls. RESULTS: The frequencies of f (FokI), b (BsmI), t (TaqI), and a (ApaI) alleles were: 55.6%, 27.3%, 62.1%, and 44.95% in the patient group, respectively and 42%, 29.5%, 54.5%, and 46.0% in the control group, respectively. Analysis of the results indicated that there was a positive association between the frequency of FokI genotypes with gastric cancer risk (p= 0.021). However, no statistically significant association of BsmI, Taq1, and ApaI polymorphisms of VDR was detected in gastric patients when compared with healthy individuals. CONCLUSION: VDR-FokI polymorphism could increase the risk of GC development and predispose to the disease by mechanisms.

Medicinal Plants Extracts with Antiangiogenic Activity: Where Is the Link?

Angiogenesis is a strictly controlled process defined as the formation of new blood vessels essential for certain physiologic and pathologic conditions where the latter includes tumor growth, development, and metastasis. Thus, inhibiting angiogenesis along with other anticancer strategies such as chemotherapy seems to be invaluable for reaching an optimal outcome in cancer patients. It has been shown that some natural plant-derived compounds are capable of preventing the formation of these new blood vessels in the tumor and also inhibit the proliferation and growth of the cancer cells. In this review, we intend to introduce plants with anti-angiogenic properties and discuss their related features.

Cancer cells change their glucose metabolism to overcome increased ROS: One step from cancer cell to cancer stem cell?

Cancer cells can adapt to low energy sources in the face of ATP depletion as well as to their high levels of ROS by altering their metabolism and energy production networks which might also have a role in determining cell fate and developing drug resistance. Cancer cells are generally characterized by increased glycolysis. This is while; cancer stem cells (CSCs) exhibit an enhanced pentose phosphate pathway (PPP) metabolism. Based on the current literature, we suggest that cancer cells when encountering ROS, first increase the glycolysis rate and then following the continuation of oxidative stress, the metabolic balance is skewed from glycolysis to PPP. Therefore, we hypothesize in this review that in cancer cells this metabolic deviation during persistent oxidative stress might be a sign of cancer cells' shift towards CSCs, an issue that might be pivotal in more effective targeting of cancer cells and CSCs.

Contribution and prognostic value of TSGA10 gene expression in patients with acute myeloid leukemia (AML).

BACKGROUND: Different studies have investigated TSGA10 expression in various cancerous tissues but, so far no study has been conducted on newly diagnosed (ND) AML patients. The association of TSGA10 gene expression with hypoxia inducible factor (HIF) and angiogenic factors has remained to be fully elucidated and is still a controversial issue. The present study was designed to investigate this association in patients newly diagnosed with AML. METHODS: We evaluated TSGA10, HIF-1α and VEGF mRNA levels in ND AML patients and healthy subjects using real-time PCR technique. Data were analyzed via comparative Livak method. RESULTS: Based on the results of this study, TSGA10 gene expression was decreased in 28 out of 30 (93.3%) samples while VEGF and HIF-1α expression levels were increased in all ND AML patients compared to healthy controls. Diagnostic evaluation was performed by receiver operating characteristic (ROC) curve and area under the curve (AUC) calculation. Respectively, using cut-off relative quantification of 1.604, 0.0329, and 0.0042, the sensitivity values of TSGA10, VEGF, and HIF-1α gene expression were 86.7%, 90%, and 100%. Also, specificity values were 100%, 100% and 100%, respectively. TSGA10 expression was shown to be reduced in ND AML patients compared with healthy subjects and we found a negative correlation between TSGA10 and VEGF expression. CONCLUSIONS: Since TSGA10 interacts with HIF-1 and affects its transcriptional activity, in ND AML patients with decreased TSGA10 expression, VEGF expression was high suggesting a TSGA10 mediated regulation of HIF-1 target genes. Altogether, the current study showed that TSGA10 could be considered as a tumor suppressor in AML patients.

Anti-angiogenesis effect of ß-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive properties under experimental model.

Angiogenesis is a process through which new capillaries are formed from pre-existing ones, which contributes significantly to the pathogenesis of numerous diseases, such as cancer and chronic inflammatory disorders. The ß-D-mannuronic acid (M2000) is a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive effects and is a matrix metalloproteinase (MMP) inhibitor. This research aimed to study the anti-angiogenesis effects of M2000 under in vitro and in vivo models. The cytotoxic and anti-proliferative effects of M2000 were examined using the trypan blue method and the MTT assay, respectively. The 3D collagen-cytodex model and the chick chorioallantoic membrane (CAM) assay were then used to evaluate the anti-angiogenesis property of M2000. Cytotoxicity assay revealed that M2000 (at concentrations of less than 100 µg/mL) had no cytotoxic effect on human umbilical vein endothelial cells (HUVECs). It was also illustrated that M2000 had little or no anti-proliferative effect on HUVECs. In addition, the anti-angiogenesis effects of M2000 were shown to be marginal in the in vitro model and both significant and dose-dependent in the in vivo status. This study showed that M2000 could be considered as an anti-angiogenic molecule which more likely exerts its activity mainly via indirect effects on endothelial cells and its anti-inflammatory effects may partly be attributable to its anti-angiogenic activity. Therefore, it could be recommended as a candidate for prevention and treatment of cancer, chronic inflammatory diseases, and other angiogenesis-related disorders.

Anti-angiogenic potential of trypsin inhibitor purified from Cucumis melo seeds: Homology modeling and molecular docking perspective.

Melons have a good source of protease inhibitors. Its fruit and seeds have been used as a traditional medicine. However, its effects on angiogenesis and mechanism of its action remain elusive. Herein trypsin inhibitor from aqueous extract of C. melo seeds (TICMS) was purified. Its effects on different steps of angiogenesis were evaluated. Also, we examined its effects on migration and angiogenesis of endothelial cells. Three dimensional model of TICMS protein was accurately built in which TICMS docked to αVß3 integrin and VEGFR1. Electrophoresis analysis of the purified protein revealed a single band with a molecular mass of about 3kDa. Treatment with TICMS at six doses resulted in a significant decrease of endothelial cell proliferation with an IC50 value of about 20µg/ml. Tubulogenesis assay revealed that a dose dependent anti-angiogenic activity of TICMS (5-40µg/ml). Also, TICMS had inhibitory effects on VEGF, MMP-2 and MMP-9 secretion. Our docking result speculated that TICMS could bind to the cleft between the αVß3 integrin and it able to decrease the activity of this receptor. The TICMS was also able to interact with VEGFR1 receptor, but with low probability. Based on our study, TICMS could be used as a specific angiogenesis inhibitor.