• The Korean Journal of Physiology and Pharmacology
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• 제24권5호
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• pp.423-431
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• 2020

This study aimed to evaluate the effect of curcumin on brain hypoxic-ischemic (HI) damage in neonatal rats and whether the phosphoinositide 3-kinase (PI3K)/Akt/vascular endothelial growth factor (VEGF) signaling pathway is involved. Brain HI damage models were established in neonatal rats, which received the following treatments: curcumin by intraperitoneal injection before injury, insulin-like growth factor 1 (IGF-1) by subcutaneous injection after injury, and VEGF by intracerebroventricular injection after injury. This was followed by neurological evaluation, hemodynamic measurements, histopathological assessment, TUNEL assay, flow cytometry, and western blotting to assess the expression of p-PI3K, PI3K, p-Akt, Akt, and VEGF. Compared with rats that underwent sham operation, rats with brain HI damage showed remarkably increased neurological deficits, reduced right blood flow volume, elevated blood viscosity and haematocrit, and aggravated cell damage and apoptosis; these injuries were significantly improved by curcumin pretreatment. Meanwhile, brain HI damage induced the overexpression of p-PI3K, p-Akt, and VEGF, while curcumin pretreatment inhibited the expression of these proteins. In addition, IGF-1 treatment rescued the curcumin-induced down-regulated expression of p-PI3K, p-Akt, and VEGF, and VEGF overexpression counteracted the inhibitory effect of curcumin on brain HI damage. Overall, pretreatment with curcumin protected against brain HI damage by targeting VEGF via the PI3K/Akt signaling pathway in neonatal rats.

• Genomics & Informatics
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• 제19권1호
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• pp.6.1-6.10
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• 2021

Vascular endothelial growth factor (VEGF) is expressed at elevated levels by most cancer cells, which can stimulate vascular endothelial cell growth, survival, proliferation as well as trigger angiogenesis modulated by VEGF and VEGFR (a tyrosine kinase receptor) signaling. The angiogenic effects of the VEGF family are thought to be primarily mediated through the interaction of VEGF with VEGFR-2. Targeting this signaling molecule and its receptor is a novel approach for blocking angiogenesis. In recent years virtual high throughput screening has emerged as a widely accepted powerful technique in the identification of novel and diverse leads. The high resolution X-ray structure of VEGF has paved the way to introduce new small molecular inhibitors by structure-based virtual screening. In this study using different alkaloid molecules as potential novel inhibitors of VEGF, we proposed three alkaloid candidates for inhibiting VEGF and VEGFR mediated angiogenesis. As these three alkaloid compounds exhibited high scoring functions, which also highlights their high binding ability, it is evident that these alkaloids can be taken to further drug development pipelines for use as novel lead compounds to design new and effective drugs against cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제13권5호
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• pp.2009-2014
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• 2012

Objective: Taspine, isolated from Radix et Rhizoma Leonticis has demosntrated potential proctiective effects against cancer. Tas13D, a novel taspine derivative synthetized by structure-based drug design, have been shown to possess interesting biological and pharmacological activities. The current study was designed to evaluate its antiproliferative activity and underlying mechanisms. Methods: Antiproliferative activity of tas13D was evaluated by xenograft in athymic mice in vivo, and by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and cell migration assays with human liver cancer (SMMC-7721) cell lines in vitro. Docking between tas13D and VEGFR and EGFR was studied by with a Sybyl/Surflex module. VEGF and EGF and their receptor expression was determined by ELISA and real-time PCR methods, respectively. Results: Our present study showed that tas13D inhibited SMMC-7721 xenograft tumor growth, bound tightly with the active site of kinase domains of EGFR and VEGFR, and reduced SMMC-7721 cell proliferation (IC=34.7 ${\mu}mol/L$) and migration compared to negative controls. VEGF and EGF mRNAs were significantly reduced by tas13D treatment in a dose-dependent manner, along with VEGF and EGF production. Conclusion: The obtained results suggest that tas13D inhibits tumor growth and cell proliferation by inhibiting cell migration, downregulating mRNA expression of VEGF and EGF, and decreasing angiogenic factor production. Tas13D deserves further consideration as a chemotherapeutic agent.

• 통합자연과학논문집
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• 제10권3호
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• pp.141-147
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• 2017

Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis, which is the formation of new blood vessels from pre-existing vessels. Consequently, blocking of the vascular endothelial growth factor receptor (VEGFR-2) by small molecule inhibitors leads to the inhibition of cancer induced angiogenesis. In this study, we performed a two dimensional quantitative structure activity relationship (2D-QSAR) study of 38 N-Phenyl-N'-{4-(4-quinolyloxy) phenyl} urea derivatives as VEGFR-2 inhibitors based on hologram quantitative structure-activity (HQSAR). The model developed showed reasonable $q^2=0.521$ and $r^2=0.932$ values indicating good predictive ability and reliability. The atomic contribution map analysis of most active compound (compound 7) indicates that hydrogen and oxygen atoms in the side chain of ring A and oxygen atom in side chain of ring C contributes positively to the activity of the compounds. The HQSAR model developed and the atomic contribution map can serve as a guideline in designing new compounds for VEGFR-2 inhibition.

• Biomolecules & Therapeutics
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• 제31권4호
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• pp.456-465
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• 2023

Cervical tumors represent a prevalent form of cancer affecting women worldwide; current treatment options involve surgery, radiotherapy, and chemotherapy. Angiogenesis, the process of new blood vessel formation, is a crucial factor in cervical tumor growth. The molecular mechanisms underlying the effects of the liver kinase B1 (LKB1/STK11) tumor suppressor protein on tumor angiogenesis have not been elucidated. Therefore, we investigated the role of LKB1 in cervical tumor angiogenesis both in vitro and in vivo in this study. Our results demonstrated that LKB1 inhibited cervical tumor angiogenesis by suppressing the expression of angiogenesis-related factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α. LKB1 directly affected both carcinoma and vascular endothelial cells, resulting in a significant reduction in tumor growth and angiogenesis. Furthermore, LKB1 was found to bind to VEGF receptor 2 (VEGFR-2) and target the VEGFR-2-mediated protein kinase B/mechanistic target of rapamycin signaling pathway in endothelial cells, thereby reducing cervical tumor growth and angiogenesis. Our study provides new insights into the molecular mechanisms underlying the anti-tumor and anti-angiogenic effects of LKB1 in cervical cancer. These findings will help develop new therapeutic strategies for cervical cancer.

• Journal of Veterinary Science
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• 제25권1호
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• pp.1.1-1.15
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• 2024

Background: Axitinib, a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR) tyrosine kinase 1,2 and 3, is used in chemotherapy because it inhibits tumor angiogenesis by blocking the VEGF/VEGFR pathway. In veterinary medicine, attempts have been made to apply tyrosine kinase inhibitors with anti-angiogenic effects to tumor patients, but there are no studies on axitinib in canine mammary gland tumors (MGTs). Objectives: This study aimed to confirm the antitumor activity of axitinib in canine mammary gland cell lines. Methods: We treated canine MGT cell lines (CIPp and CIPm) with axitinib and conducted CCK, wound healing, apoptosis, and cell cycle assays. Additionally, we evaluated the expression levels of angiogenesis-associated factors, including VEGFs, PDGF-A, FGF-2, and TGF-β1, using quantitative real-time polymerase chain reaction. Furthermore, we collected canine peripheral blood mononuclear cells (PBMCs), activated them with concanavalin A (ConA) and lipopolysaccharide (LPS), and then treated them with axitinib to investigate changes in viability. Results: When axitinib was administered to CIPp and CIPm, cell viability significantly decreased at 24, 48, and 72 h (p < 0.001), and migration was markedly reduced (6 h, p < 0.05; 12 h, p < 0.005). The apoptosis rate significantly increased (p < 0.01), and the G2/M phase ratio showed a significant increase (p < 0.001). Additionally, there was no significant change in the viability of canine PBMCs treated with LPS and ConA. Conclusion: In this study, we confirmed the antitumor activity of axitinib against canine MGT cell lines. Accordingly, we suggest that axitinib can be applied as a new treatment for patients with canine MGTs.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3419-3423
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• 2013

Of all gynecologic cancers, endometrial cancer is the most common cancer in the US and Europe. In addition, it is presently the second most common gynecologic cancer in the world. As a result of increasing menopausal, obese and tamoxifen use women, the incidence of the cancer seems to be on the increase. Surgery is the major treatment, whereas postoperative radiation therapy in high-intermediate risk patients many prevent locoregional recurrence. Adjuvant chemotherapy can improve progression free survival in advanced or recurrent cancers. Molecular targeted therapies are now a focus of attention including anti-vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR) inhibitor and tyrosine kinase inhibitor (TKI). They may provide useful future strategies for control of endometrial malignancies in developing countries and across the world.

• 생명과학회지
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• 제33권9호
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• pp.703-712
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• 2023

기존 혈관에서 새로운 혈관을 형성하는 혈관 신생은 혈관 신생 조절인자에 의해 조절되는 다단계 과정이며 배아 발달, 만성 염증 및 상처 복구를 포함한 다양한 생리학적 과정에 필수적이다. 혈관 신생의 조절장애는 암, 자가 면역 질환, 류마티스 관절염, 심혈관 질환 및 상처 치유 지연과 같은 많은 질병을 유발한다. 그러나 효과적인 혈관신생 억제 약물은 제한되어 있으며, 최근 연구에서는 천연 자원에서 잠재적인 약물후보를 식별하는 데 중점을 두고 있다. 예를 들어, 해양 천연물은 항암, 항산화, 항염증, 항바이러스 및 상처 치유 효과를 입증했다. 따라서 본 연구에서는 톳(갈조류) 추출물의 혈관 신생 억제 효과를 확인했습니다. H. fusiformis 추출물은 인간 제대 정맥 내피 세포(HUVECs)에서 세포 이동, 침윤 및 관 형성을 억제하며, 동시에 Matrigel 겔 플러그 분석을 통해 생체 내 혈관 신생을 억제를 확인했다. 또한, 톳 추출물 처리 후 VEGF, Erk, Akt의 활성이 감소하는 것을 확인했다. 이 결과를 토대로 H. fusiformis 추출물이 in vitro 및 in vivo 혈관 신생을 억제함을 시사한다.

• 생명과학회지
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• 제34권6호
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• pp.399-407
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• 2024

혈관신생은 기존 혈관에서 새로운 혈관을 형성하는 과정이며, 이 현상은 성장, 치유, 월경주기의 변화 중에 발생한다. 종양의 경우, 혈관신생은 원발성 종양의 지속적인 성장, 전이 촉진, 전이성 종양 성장 지원 및 암 진행에 중요한 복잡하고 다면적인 과정이다. 혈관신생 장애는 암 발병, 자가면역 질환, 류마티스 관절염, 심혈관 질환 및 상처 치유 지연을 초래할 수 있다. 현재 유효한 혈관신생 억제약물은 제한된 수에 불과하다. 최근 연구에 따르면 해양 천연물이 혈관신생 억제효과를 나타내는 것으로 보고되고 있다. 이전 연구에서 Hizikia fusiformis의 핵산 추출물(HFC)이 in vitro 및 in vivo에서 혈관 신생 억제효과를 확인하고 보고하였다. 본 연구의 목적은 H. fusiformis의 클로로포름 추출물(HFC)의 혈관신생 억제 효과를 확인하는 것이다. HFC가 세포 이동, 침입 및 관 형성을 포함하여 HUVEC 세포에 미치는 영향을 조사하였고, 또한 마우스 Matrigel 겔 플러그 분석을 통해 생체 내 혈관 신생 억제 효과도 조사하였다. 또한 HFC 처리 후 혈관신생에 중요한 인자인 VEGF, FGFR의 발현이 억제되고, Erk, Akt의 활성이 감소하는 것을 확인하였다. 이러한 결과는 해양갈조류 톳(H. fusiformis)의 클로르포름 추출물이 in vitro 및 in vivo 혈관 신생을 억제함을 보여준다.

• Molecules and Cells
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• 제38권6호
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• pp.528-534
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• 2015

Hypoxia-inducible factor (HIF) is a key regulator of tumor growth and angiogenesis. Recent studies have shown that, BIX01294, a G9a histone methyltransferase (HMT)-specific inhibitor, induces apoptosis and inhibits the proliferation, migration, and invasion of cancer cells. However, not many studies have investigated whether inhibition of G9a HMT can modulate HIF-$1{\alpha}$ stability and angiogenesis. Here, we show that BIX01294 dose-dependently decreases levels of HIF-$1{\alpha}$ in HepG2 human hepatocellular carcinoma cells. The half-life of HIF-$1{\alpha}$, expression of proline hydroxylase 2 (PHD2), hydroxylated HIF-$1{\alpha}$ and von Hippel-Lindau protein (pVHL) under hypoxic conditions were decreased by BIX01294. The mRNA expression and secretion of vascular endothelial growth factor (VEGF) were also significantly reduced by BIX01294 under hypoxic conditions in HepG2 cells. BIX01294 remarkably decreased angiogenic activity induced by VEGF in vitro, ex vivo, and in vivo, as demonstrated by assays using human umbilical vein endothelial cells (HUVECs), mouse aortic rings, and chick chorioallantoic membranes (CAMs), respectively. Furthermore, BIX01294 suppressed VEGF-induced matrix metalloproteinase 2 (MMP2) activity and inhibited VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), focal adhesion kinase (FAK), and paxillin in HUVECs. In addition, BIX01294 inhibited VEGF-induced formation of actin cytoskeletal stress fibers. In conclusion, we demonstrated that BIX01294 inhibits HIF-$1{\alpha}$ stability and VEGF-induced angiogenesis through the VEGFR-2 signaling pathway and actin cytoskeletal remodeling, indicating a promising approach for developing novel therapeutics to stop tumor progression.