Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics?

Anwar, Sirajudheen; Malik, Jonaid Ahmad; Ahmed, Sakeel; Kameshwar, Verma Abhishek; Alanazi, Jowaher; Alamri, Abdulwahab; Ahemad, Nafees

doi:10.3390/molecules27227668

Cited by 16 publications

(15 citation statements)

References 126 publications

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“…Many studies have reported the promising pharmacological properties of plant-based metabolites in in vitro in cell lines and in vivo in animal models. Plant based remedies have antioxidant, apoptosis-promoting effects, and can attenuate cell proliferation, metastasis (cell aggregation, migration, adhesion), and angiogenesis (Park et al, 2021;Anwar et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells

Abdallah,

Shaito,

Badran

et al. 2024

Front. Pharmacol.

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Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.

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Section: Discussionmentioning

confidence: 99%

Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells

Abdallah,

Shaito,

Badran

et al. 2024

Front. Pharmacol.

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“…These concepts require additional investigation through subsequent studies for convincing results [ 125 ]. As possible therapeutic targets for stopping epithelial–mesenchymal transition (EMT) to stop cancer spread, cancer-associated fibroblasts (CAFs) encourage EMT remolding [ 126 ]. Although they can treat regions of the body that other delivery systems cannot reach and deliver therapies, there are difficulties in clinically translating nanoparticle-based medication delivery for BC [ 127 ].…”

Section: Future Prospectsmentioning

confidence: 99%

Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment

Shinde

Ahmed

Malik

et al. 2023

Biology

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The death rate from breast cancer (BC) has dropped due to early detection and sophisticated therapeutic options, yet drug resistance and relapse remain barriers to effective, systematic treatment. Multiple mechanisms underlying miRNAs appear crucial in practically every aspect of cancer progression, including carcinogenesis, metastasis, and drug resistance, as evidenced by the elucidation of drug resistance. Non-coding RNAs called microRNAs (miRNAs) attach to complementary messenger RNAs and degrade them to inhibit the expression and translation to proteins. Evidence suggests that miRNAs play a vital role in developing numerous diseases, including cancer. They affect genes critical for cellular differentiation, proliferation, apoptosis, and metabolism. Recently studies have demonstrated that miRNAs serve as valuable biomarkers for BC. The contrast in the expression of miRNAs in normal tissue cells and tumors suggest that miRNAs are involved in breast cancer. The important aspect behind cancer etiology is the deregulation of miRNAs that can specifically influence cellular physiology. The main objective of this review is to emphasize the role and therapeutic capacity of tumor suppressor miRNAs in BC and the advancement in the delivery system that can deliver miRNAs specifically to cancerous cells. Various approaches are used to deliver these miRNAs to the cancer cells with the help of carrier molecules, like nanoparticles, poly D, L-lactic-co-glycolic acid (PLGA) particles, PEI polymers, modified extracellular vesicles, dendrimers, and liposomes. Additionally, we discuss advanced strategies of TS miRNA delivery techniques such as viral delivery, self-assembled RNA-triple-helix hydrogel drug delivery systems, and hyaluronic acid/protamine sulfate inter-polyelectrolyte complexes. Subsequently, we discuss challenges and prospects on TS miRNA therapeutic delivery in BC management so that miRNAs will become a routine technique in developing individualized patient profiles.

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“…In addition to their ndings, we found out that eugenol can bind more effectively with the hub proteins such as HSP90AA1, ESR1, CASP3 and IGF-1R than any other selected compounds. HSP90 targets multiple signaling pathways by disrupting metastatic proteins thus, inhibiting epithelial to mesenchymal transition in cancer cells (Anwar et al 2022;Zhang et al 2021). Type-I insulin like growth factor receptor is a tyrosine kinase receptor which is over expressed in many types of cancer processes such as cell growth, cell proliferation, cell differentiation, apoptosis, and angiogenesis.…”

Section: Multitarget Molecular Docking Investigationmentioning

confidence: 99%

Exploring Mechanism of Actions for Eugenol and Beta- Caryophyllene to Combat Colorectal Cancer Chemotherapy Using Network Pharmacology

Trivedi

Rathaur

Parmar

et al. 2023

Preprint

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Background: Major deaths due to colorectal cancer (CRC) arise from the metastatic dissemination of primary tumors, which is related to molecules contributing to metastatic phenotype, the pathways they control, and the genes they regulate. Purpose: To evaluate the effect of eugenol (EUG) and beta-caryophyllene (BCP) in combination with 5-fluorouracil in-vitro cytotoxic activity and in-silico method. Methods: We tested the compounds on human colorectal cancer cell line HCT116 for the combined effect of 5-FU with EUG and BCP in in-vitro MTT assay. The pharmacokinetic assessment was carried out through in-silico ADMET analysis. Compound-Disease-Target (C-D-T) network were constructed against metastatic Colorectal cancer (mCRC) from which the hub proteins were selected for molecular docking studies. Enrichment analysis for the key targets was explored for gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways involved in mCRC to explore their functional role in human body for EUG, BCP and 5-FU. Results: ADMET analysis showed that both the compounds follow the rule of five with good bioavailability thus, the compounds were found to be in the acceptable range by following drug-likeness properties. MTT assay revealed in-vitrocytotoxic effects of all three compounds and a significant reduction in IC50 values (p < 0.05) when treated the cells in combination thereby giving synergistic effects (CI < 1) represented by the Fa-CI plot. C-D-T network showed that EUG, BCP, and 5-FU target 58, 24, and 49 proteins of metastatic CRC, out of which 11 target proteins were intersected in the Venn diagram. The merged C-D-T network of these three compounds showed 84 target proteins of CRC from which 16 were selected based on their edge count which includes HSP90AA1, IGF-1R, ESR1, and CASP3. These were further screened in molecular docking which depicted that EUG, BCP, and 5-FU inhibited the C-D-T network’s core target protein HSP90AA1 (Heat shock protein-90 alpha) more effectively than any other proteins. Conclusion: Our data revealed multitarget strategy to increase the effectiveness of the drug 5-FU by reducing its dosage when combined with natural phytocomponents EUG and BCP. Here, the synergism also proved effective against mCRC.

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Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics?

Cited by 16 publications

References 126 publications

Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells

Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells

Therapeutic Delivery of Tumor Suppressor miRNAs for Breast Cancer Treatment

Exploring Mechanism of Actions for Eugenol and Beta- Caryophyllene to Combat Colorectal Cancer Chemotherapy Using Network Pharmacology

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