Elaeagnus Angustifolia Plant Extract inhibits Epithelial- mesenchymal Transition in Human Colorectal Cancer via β-catenin/JNK signaling Pathways

Elaeagnus angustifolia (EA) is a traditional plant that has been used as an alternative medicine for centuries. EA roles as anti-cancer has been investigated against different types of cancer, however, its effect against human cancer has not been investigated yet. Therefore, we investigated the aqueous EA extract effect on colorectal cancer (CRC) cell lines (HCT-116 and LoVo) and examined its underlying mechanisms of action in vitro. Our results showed that EA inhibited cell proliferation and disturbed cell-cycle progression of both CRC cell lines comparing to the control. Moreover, EA extract significantly reduced colony formation in addition to migration and invasion ability of both CRC cell lines this is confirmed by significant upregulation of E-cadherin and Pan-cadherin as well as down regulation of Vimentin. Further, β-catenin/JNK signaling pathway was analyzed and we found that EA extract significantly blocked the activity of total and phosphorylated β-catenin and JNK1/2/3.Scopu

Effects of neratinib on angiogenesis and the early stage of the embryo using chicken embryo as a model

Angiogenesis is the process of forming new blood capillaries from pre-existing vessels. Even though it is essential during normal development, it plays a major role in cancer progression. Neratinib is a pan-human epidermal growth factor receptor (HER) inhibitor that has recently been approved for the treatment of HER2-positive breast cancer. However, its effects on angiogenesis and embryogenesis remain unknown. This study examined the antiangiogenic effects of neratinib using the chorioallantoic membrane (CAM) of chicken embryos. We also evaluated neratinib’s toxicity during the early stages of normal development using the chicken embryos, primary embryonic fibroblasts (EFBs), and human umbilical vein endothelial cells (HUVEC). Our findings revealed that neratinib significantly inhibited the CAM angiogenesis compared to controls by reducing vessel percentage area and the average vessel length. Furthermore, neratinib downregulated vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. At lower concentrations, neratinib was well-tolerated during early stages of normal development. Additionally, EFBs treated with neratinib showed no morphological or viability changes when compared to controls. However, at the highest concentration tested, neratinib treatment reduced HUVEC cell viability. This effect may be associated with the dysregulation of key apoptotic genes, including caspase-3, caspase-8, caspase-9, and the B-cell lymphoma 2 (Bcl2) gene. Our findings indicate a novel potential application of neratinib as an antiangiogenic agent, exhibiting tolerable toxicity in the early stages of embryogenesis

Elaeagnus angustifolia Plant Extract Induces Apoptosis via P53 and Signal Transducer and Activator of Transcription 3 Signaling Pathways in Triple-Negative Breast Cancer Cells

Elaeagnus angustifolia (EA) is used as an alternative medicine in the Middle East to manage numerous human diseases. We recently reported that EA flower extract inhibits cell proliferation and invasion of human oral and HER2-positive breast cancer cells. Nevertheless, the outcome of EA extract on triple-negative breast cancer (TNBC) cells has not been explored yet. We herein investigate the effect of the aqueous EA extract (100 and 200 μl/ml) on two TNBC cell lines (MDA-MB-231 and MDA-MB-436) for 48 h and explore its underlying molecular pathways. Our data revealed that EA extract suppresses cell proliferation by approximately 50% and alters cell-cycle progression of these two cancer cell lines. Additionally, EA extract induces cell apoptosis by 40–50%, accompanied by the upregulation of pro-apoptotic markers (Bax and cleaved caspase-8) and downregulation of the anti-apoptotic marker, Bcl-2. Moreover, EA extract inhibits colony formation compared to their matched control. More significantly, the molecular pathway analysis of EA-treated cells revealed that EA extract enhances p53 expression, while inhibiting the expression of total and phosphorylated Signal Transducer and Activator Of Transcription 3 (STAT3) in both cell lines, suggesting p53 and STAT3 are the main key players behind the biological events provoked by the extract in TNBC cells. Our findings implicate that EA flower extract may possess an important potential as an anticancer drug against TNBC.Grants from Qatar University: # QUST-1-CPH-2021-22, QUCP-CMED-22/23-529, and QUCG-CMED-20/21-2

Haematococcus pluvialis Microalgae Extract Inhibits Proliferation, Invasion, and Induces Apoptosis in Breast Cancer Cells

Breast cancer (BC) is the most common malignant cancer in females worldwide. Drug resistance, toxicity, and the failure of current therapies to completely cure BC has challenged conventional medicine. Consequently, complementary alternative medicine has become popular due to its safety and efficacy. Haematococcus pluvialis (H. pulvialis) is a green microalga living in fresh water, and its crude extract is rich of bioactives, including carotenoids, known to inhibit cancer cell growth. In the present study, we investigated the effects of a methanol crude extract called "T1" of H. pulvialis on cell growth and migration/invasion of the BC cell line MDA-MB-231 in comparison to the fibroblast control cells. TI significantly suppressed BC cell growth, inhibited migration and invasion and induced apoptosis. Interestingly, apoptosis was mediated by a significant loss of mutant p53 protein, and increased Bax/Bcl2 ratio. Our findings support our hypothesis that T1 exerts its anti-cancer effects by inhibiting BC invasion and inducing apoptosis mediated, at least, via the p53/Bax/Bcl2 pathway. Ongoing experiments aim to identify the molecular mechanisms underpinning T1-inhibited BC cell invasion using pre-designed metastasis gene-based array method.This research was funded by the Qatar University Internal Grant Nos. QUST-2-CAS-2021-137 and QUST-2-CAS-2021-138.Scopu

Elaeagnus Angustifolia extract inhabits cell invasion of human colorectal cancer cells and increases the survival rate of the Drosophila colon cancer model

Colorectal cancer (CRC), the third most common type of cancer in the world, is an aggressive type of cancer with high tendency to metastasize and invade to other tissues and distant organs. Traditional CRC treatment regimen includes 5-fluorouracil (5-FU); however, tumors develop a resistance against these drugs, apart from the severe side effects that develop upon these therapies. Nowadays, traditional medicinal plants are the focus of increased interest as a source for new potential drugs, particularly those that serve as anti-cancerous agents. Elaeagnus angustifolia (EA) is a medicinal plant that can be used traditionally to manage several human ailments including cancers especially oral and HER2-positive breast cancer as recently reported by our group. However, the effect of EA flower extract on human CRC has not been investigated yet. Therefore, EA effect was explored in vitro using KRAS CRC cell lines (HCT-116 and LoVo) and in vivo using transgenic Drosophila melanogaster model for KRAS gene, which is known to develop CRC. Our results from the in vitro investigations revealed that EA flower extract significantly inhibits cell motility and invasion in addition to colony formation. Moreover, we found that EA extract modulates the epithelial-mesenchymal transition (EMT) event and its related genes; EMT is a known hallmark of cancer invasion and metastasis. More significantly, our in vivo data pointed out that EA extract increases the survival rate of KRAS mutation D. melanogaster model. Our findings implicate that EA extract may possess chemo-preventive effects against human CRC

THE EFFECT OF NATURAL AND SYNTHETIC COMPOUNDS ON COLORECTAL CANCER: IN VITRO AND IN VIVO STUDIES

Colorectal cancer (CRC) is one of the deadliest malignancies in the world. Despite improved treatment, CRC incidence and mortality rates have been increasing lately. Current conventional therapies are associated with severe side effects that affect patients' quality of life. Drug resistance, severe pain, hair loss, and blood abnormalities are the most common side effects. Therefore, novel, and safe alternatives are required to control metastasis and prevent CRC with minimum or no side effects. Recently, natural products became an attractive target as a safe resource for anticancer agents. Flavonoids are a group of biologically active compounds naturally found in a wide range of human dietary. Additionally, flavonoids from natural and synthetic sources, showed significant therapeutic effects against CRC. Elaeagnus Angustifolia (EA) is a natural resource for flavonoids traditionally used to treat different illnesses. Another resource for flavonoids is synthetic chalcone analogs. Previous work from our team explored the effect of EA and chalcone compounds against various types of cancer. In this study, we sought to particularly illustrate the impact of the EA flower’s aqueous extract and the nitrogen-based-synthetically designed chalcone analogs (DK13 and DK14) and their underlying mechanisms of action on CRC using in vitro (the human CRC cell lines [-116 and LoVo]) and in vivo (the Drosophila melanogaster Ras mutant fly lines) model systems. Our results showed that EA extract inhibits cell proliferation and alters cell cycle progression of both CRC cell lines as compared to the control group. Moreover, EA extract significantly reduces colony formation and cell invasive ability of HCT-116 and LoVo cell lines; a phenotype accompanied by a significant upregulation of E-cadherin and a downregulation of vimentin and β-catenin, which are important epithelialmesenchymal transition (EMT) biomarkers. Also, and as detected in our in vivo model, EA-treated Ras85D mutant fly lines exhibited a significantly increased survival rate as compared to their control. Furthermore, molecular pathway analysis in vitro revealed a significant suppression in total and phosphorylated EGFR and AKT expression in EAtreated cells as compared to controls, suggesting the EGFR-RAS and PI3K-AKT pathways as key molecular pathway targeted by EA to control ongoing oncogenic events. Along this, our data related to DK13 and DK14 also revealed that these compounds inhibit cell proliferation and deregulate cell-cycle progression in both cell lines. Additionally, DK13 and DK14 significantly reduce cell invasion and colony formation of both cell lines compared to the action of conventional anticancer 5'fluorouracil (5-FU) and DMSO-treated control. This was translated into a significant increase in the survival rates of D. melanogaster Ras85D mutant fly lines as compared to their controls. Moreover, the molecular pathway analysis of chalcone- treated cells revealed an inhibitory effect of DK13 and DK14 on the expression patterns of both AKT and mTOR, highlighting RAS/MAPK and PI3K/AKT/mTOR pathways as key molecular pathway targeted by DK13 and DK14 to control ongoing oncogenic events. Collectively, our study findings demonstrate an apparent anticancer effect of EA extract and chalcone compounds on CRC, presenting EA, Dk13, and Dk14 as promising chemotherapeutic agents

The effect of novel nitrogen-based chalcone analogs on colorectal cancer cells: Insight into the molecular pathways

In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of β-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through β-catenin/Akt/mTOR signaling pathways.This research was funded by Qatar University internal grants and QNRF: QUCP-CMED-22/23–529 and QUCG-CMED-20/21-2 , QUCG-CPH- 22/23–510 and UREP28-022-3-005