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20 pages, 5766 KiB

Open AccessArticle

Tannic Acid and Ethyl Gallate Potentialize Paclitaxel Effect on Microtubule Dynamics in Hep3B Cells

by Jessica Nayelli Sánchez-Carranza, Mariano Redondo-Horcajo, Isabel Barasoain, Ever Angel Escobar-Aguilar, César Millán-Pacheco, Laura Alvarez, Enrique Salas Vidal, J. Fernando Diaz and Leticia Gonzalez-Maya

Pharmaceuticals 2023, 16(11), 1579; https://doi.org/10.3390/ph16111579 - 8 Nov 2023

Cited by 1 | Viewed by 1780

Abstract

Among broad-spectrum anticancer agents, paclitaxel (PTX) has proven to be one of the most effective against solid tumors for which more specific treatments are lacking. However, drawbacks such as neurotoxicity and the development of resistance reduce its therapeutic efficacy. Therefore, there is a [...] Read more.

Among broad-spectrum anticancer agents, paclitaxel (PTX) has proven to be one of the most effective against solid tumors for which more specific treatments are lacking. However, drawbacks such as neurotoxicity and the development of resistance reduce its therapeutic efficacy. Therefore, there is a need for compounds able to improve its activity by synergizing with it or potentiating its effect, thus reducing the doses required. We investigated the interaction between PTX and tannins, other compounds with anticancer activity known to act as repressors of several proteins involved in oncological pathways. We found that both tannic acid (TA) and ethyl gallate (EG) strongly potentiate the toxicity of PTX in Hep3B cells, suggesting their utility in combination therapy. We also found that AT and EG promote tubulin polymerization and enhance the effect of PTX on tubulin, suggesting a direct interaction with tubulin. Biochemical experiments confirmed that TA, but not EG, binds tubulin and potentiates the apparent binding affinity of PTX for the tubulin binding site. Furthermore, the molecular docking of TA to tubulin suggests that TA can bind to two different sites on tubulin, one at the PTX site and the second at the interface of α and β-tubulin (cluster 2). The binding of TA to cluster 2 could explain the overstabilization in the tubulin + PTX combinatorial assay. Finally, we found that EG can inhibit PTX-induced expression of pAkt and pERK defensive protein kinases, which are involved in resistance to PXT, by limiting cell death (apoptosis) and favoring cell proliferation and cell cycle progression. Our results support that tannic acid and ethyl gallate are potential chemotherapeutic agents due to their potentiating effect on paclitaxel. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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14 pages, 3438 KiB

Open AccessArticle

Involvement of PI3K/HIF-1α/c-MYC/iNOS Pathway in the Anticancer Effect of Suaeda vermiculata in Rats

by Hamdoon A. Mohammed, Mohamed G. Ewees, Nesreen I. Mahmoud, Hussein M. Ali, Elham Amin and Mohamed S. Abdel-Bakky

Pharmaceuticals 2023, 16(10), 1470; https://doi.org/10.3390/ph16101470 - 16 Oct 2023

Cited by 1 | Viewed by 1379

Abstract

Suaeda vermiculata Forssk. ex JF Gmel. (SV), a traditional known plant, has shown in vitro cytotoxic activity against HepG2 and HepG-2/ADR (doxorubicin-resistant cells) liver cell carcinoma cell lines, as well as hepatoprotection against paracetamol and carbon tetrachloride (CCl4)-induced liver injury. The current study [...] Read more.

Suaeda vermiculata Forssk. ex JF Gmel. (SV), a traditional known plant, has shown in vitro cytotoxic activity against HepG2 and HepG-2/ADR (doxorubicin-resistant cells) liver cell carcinoma cell lines, as well as hepatoprotection against paracetamol and carbon tetrachloride (CCl4)-induced liver injury. The current study evaluated the protective effect of SV, administered against N-diethylnitrosamine (NDEA)-induced HCC in rats. The possible modulatory effect of SV on the PI3K/HIF-1α/c-MYC/iNOS pathway was investigated. Sixty male adult albino rats (200 ± 10 g) were equally classified into five groups. Group I served as a control; Group 2 (SV control group) received SV (p.o., 200 mg/kg body weight); Group 3 (NDEA-administered rats) received freshly prepared NDEA solution (100 mg/L); and Groups 4 and 5 received simultaneously, for 16 weeks, NDEA + SV extract (100 and 200 mg/kg, orally). NDEA-treated rats displayed significant increases in serum levels of AFP, CEA, PI3K, malondialdehyde (MDA), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGFR), with increased liver tissue protein expression of fibrinogen concomitant and significantly decreased concentrations of antioxidant parameters (catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH)) in comparison to normal rats. On the flip side, AFP, CEA, PI3K, MDA, EGFR, and VEGFR serum levels were significantly reduced in rats that received NDEA with SV, both at low (SV LD) and high (SV HD) doses, accompanied by significant improvements in antioxidant parameters compared to the NDEA-treated group. Conclusions: SV possesses a significant hepatoprotective effect against NDEA-induced HCC via inhibiting the PI3K/HIF-1α/c-MYC/iNOS pathway, suggesting that SV could be a promising hepatocellular carcinoma treatment. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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14 pages, 3670 KiB

Open AccessArticle

Asiatic Acid Inhibits Nasopharyngeal Carcinoma Cell Viability and Migration via Suppressing STAT3 and Claudin-1

by Supitchaya Pantia, Thaned Kangsamaksin, Tavan Janvilisri and Waraporn Komyod

Pharmaceuticals 2023, 16(6), 902; https://doi.org/10.3390/ph16060902 - 19 Jun 2023

Cited by 8 | Viewed by 1963

Abstract

Nasopharyngeal carcinoma (NPC) is a prevalent cancer in Southeast Asia, but effective treatment options remain limited, and chemotherapy has a high resistance rate. Asiatic acid (AA), a triterpenoid found in Centella asiatica, has shown anticancer activity in various cancers. Therefore, this study [...] Read more.

Nasopharyngeal carcinoma (NPC) is a prevalent cancer in Southeast Asia, but effective treatment options remain limited, and chemotherapy has a high resistance rate. Asiatic acid (AA), a triterpenoid found in Centella asiatica, has shown anticancer activity in various cancers. Therefore, this study aims to investigate the anticancer effects and mechanisms of AA in NPC cell lines. The effects of AA on NPC cytotoxicity, apoptosis, and migration were determined in TW-01 and SUNE5-8F NPC cell lines. Western blot analysis was performed to evaluate the protein expression levels affected by AA. The role of AA in proliferation and migration was investigated in STAT3 and claudin-1 knockdown cells. AA inhibited NPC cell viability and migration and induced cell death by increasing cleaved caspase-3 expression. Moreover, AA inhibited STAT3 phosphorylation and reduced claudin-1 expression in NPC cells. Although knockdown of STAT3 or claudin-1 slightly reduced cell viability, it did not enhance the anti-proliferative effect of AA. However, knockdown of STAT3 or claudin-1 increased the anti-migratory effect of AA in NPC cells. These results suggest that AA can be a promising candidate for drug development against NPC. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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13 pages, 3484 KiB

Open AccessCommunication

Urtica dioica Leaf Infusion Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Cisplatin Treatment

by Guy Nafeh, Maria Abi Akl, Jad Samarani, Rawane Bahous, Georges Al Kari, Maria Younes, Rita Sarkis and Sandra Rizk

Pharmaceuticals 2023, 16(6), 780; https://doi.org/10.3390/ph16060780 - 23 May 2023

Cited by 5 | Viewed by 2991

Abstract

Urtica dioica (UD) has been widely used in traditional medicine due to its therapeutic benefits, including its anticancer effects. Natural compounds have a promising potential when used in combination with chemotherapeutic drugs. The present study explores the anticancer and anti-proliferative properties of UD [...] Read more.

Urtica dioica (UD) has been widely used in traditional medicine due to its therapeutic benefits, including its anticancer effects. Natural compounds have a promising potential when used in combination with chemotherapeutic drugs. The present study explores the anticancer and anti-proliferative properties of UD tea in combination with cisplatin on MDA-MB-231 breast cancer cells in vitro. To elucidate the effect of this combination, a cell viability assay, Annexin V/PI dual staining, cell death ELISA, and Western blots were performed. The results showed that the combination of UD and cisplatin significantly decreased the proliferation of MDA-MB-231 cells in a dose- and time-dependent manner compared to each treatment alone. This was accompanied by an increase in two major hallmarks of apoptosis, the flipping of phosphatidylserine to the outer membrane leaflet and DNA fragmentation, as revealed by Annexin V/PI staining and cell death ELISA, respectively. DNA damage was also validated by the upregulation of the cleaved PARP protein as revealed by Western blot analysis. Finally, the increase in the Bax/Bcl-2 ratio further supported the apoptotic mechanism of death induced by this combination. Thus, a leaf infusion of Urtica dioica enhanced the sensitivity of an aggressive breast cancer cell line to cisplatin via the activation of apoptosis. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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17 pages, 3228 KiB

Open AccessArticle

Alkaloid from Geissospermum sericeum Benth. & Hook.f. ex Miers (Apocynaceae) Induce Apoptosis by Caspase Pathway in Human Gastric Cancer Cells

by Mirian Letícia Carmo Bastos, João Victor Silva-Silva, Jorddy Neves Cruz, Amanda Roberta Palheta da Silva, Alexandre Augusto Bentaberry-Rosa, Gisele da Costa Ramos, José Edson de Sousa Siqueira, Márlia Regina Coelho-Ferreira, Sandro Percário, Patrícia Santana Barbosa Marinho, Andrey Moacir do Rosario Marinho, Marcelo de Oliveira Bahia and Maria Fâni Dolabela

Pharmaceuticals 2023, 16(5), 765; https://doi.org/10.3390/ph16050765 - 18 May 2023

Cited by 15 | Viewed by 2422

Abstract

Gastric cancer is among the major causes of death from neoplasia leading causes of death worldwide, with high incidence rates and problems related to its treatment. Here, we outline how Geissospermum sericeum exerts antitumor activity on the ACP02 cell line (human gastric adenocarcinoma) [...] Read more.

Gastric cancer is among the major causes of death from neoplasia leading causes of death worldwide, with high incidence rates and problems related to its treatment. Here, we outline how Geissospermum sericeum exerts antitumor activity on the ACP02 cell line (human gastric adenocarcinoma) and the mechanism of cell death. The ethanol extract and fractions, neutral fraction and alkaloid fraction, were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid (geissoschizoline N4-methylchlorine) identified by NMR. The cytotoxicity activity of the samples (ethanol extract, neutral fraction, alkaloid fraction, and geissoschizoline N4-methylchlorine) in HepG2 and VERO cells was determined by MTT. The ACP02 cell line was used to assess the anticancer potential. Cell death was quantified with the fluorescent dyes Hoechst 33342, propidium iodide, and fluorescein diacetate. The geissoschizoline N4-methylchlorine was evaluated in silico against caspase 3 and 8. In the antitumor evaluation, there was observed a more significant inhibitory effect of the alkaloid fraction (IC50 18.29 µg/mL) and the geissoschizoline N4-methylchlorine (IC₅₀ 12.06 µg/mL). However, geissoschizoline N4-methylchlorine showed lower cytotoxicity in the VERO (CC₅₀ 476.0 µg/mL) and HepG2 (CC₅₀ 503.5 µg/mL) cell lines, with high selectivity against ACP02 cells (SI 39.47 and 41.75, respectively). The alkaloid fraction showed more significant apoptosis and necrosis in 24 h and 48 h, with increased necrosis in higher concentrations and increased exposure time. For the alkaloid, apoptosis and necrosis were concentration- and time-dependent, with a lower necrosis rate. Molecular modeling studies demonstrated that geissoschizoline N4-methylchlorine could occupy the active site of caspases 3 and 8 energetically favorably. The results showed that fractionation contributed to the activity with pronounced selectivity for ACP02 cells, and geissoschizoline N4-methylchlor is a promising candidate for caspase inhibitors of apoptosis in gastric cancer. Thus, this study provides a scientific basis for the biological functions of Geissospermum sericeum, as well as demonstrates the potential of the geissoschizoline N4-methylchlorine in the treatment of gastric cancer. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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18 pages, 715 KiB

Open AccessArticle

Valorization of Punica granatum L. Leaves Extracts as a Source of Bioactive Molecules

by Sandra Marcelino, Filipa Mandim, Oludemi Taofiq, Tânia C. S. P. Pires, Tiane C. Finimundy, Miguel A. Prieto and Lillian Barros

Pharmaceuticals 2023, 16(3), 342; https://doi.org/10.3390/ph16030342 - 23 Feb 2023

Cited by 11 | Viewed by 2836

Abstract

Due to a lack of innovative valorization strategies, pomegranate processing generates a significant amount of residues with a negative environmental footprint. These by-products are a rich source of bioactive compounds with functional and medicinal benefits. This study reports the valorization of pomegranate leaves [...] Read more.

Due to a lack of innovative valorization strategies, pomegranate processing generates a significant amount of residues with a negative environmental footprint. These by-products are a rich source of bioactive compounds with functional and medicinal benefits. This study reports the valorization of pomegranate leaves as a source of bioactive ingredients using maceration, ultrasound, and microwave-assisted extraction techniques. The phenolic composition of the leaf extracts was analyzed using an HPLC-DAD-ESI/MSn system. The extracts’ antioxidant, antimicrobial, cytotoxic, anti-inflammatory, and skin-beneficial properties were determined using validated in vitro methodologies. The results showed that gallic acid, (-)-epicatechin, and granatin B were the most abundant compounds in the three hydroethanolic extracts (between 0.95 and 1.45, 0.7 and 2.4, and 0.133 and 3.0 mg/g, respectively). The leaf extracts revealed broad-spectrum antimicrobial effects against clinical and food pathogens. They also presented antioxidant potential and cytotoxic effects against all tested cancer cell lines. In addition, tyrosinase activity was also verified. The tested concentrations (50–400 µg/mL) ensured a cellular viability higher than 70% in both keratinocyte and fibroblast skin cell lines. The obtained results indicate that the pomegranate leaves could be used as a low-cost source of value-added functional ingredients for potential nutraceutical and cosmeceutical applications. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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16 pages, 3650 KiB

Open AccessArticle

Targeting Mcl-1 Degradation by Bergenin Inhibits Tumorigenesis of Colorectal Cancer Cells

by Yu Gan, Xiaoying Li, Shuangze Han, Li Zhou and Wei Li

Pharmaceuticals 2023, 16(2), 241; https://doi.org/10.3390/ph16020241 - 6 Feb 2023

Cited by 7 | Viewed by 2553

Abstract

Myeloid leukemia 1 (Mcl-1) is frequently overexpressed in human malignancies and emerged as a promising drug target. In this study, we verified the inhibitory effect of bergenin on colorectal cancer cells both in vivo and in vitro. In an in vitro setting, bergenin [...] Read more.

Myeloid leukemia 1 (Mcl-1) is frequently overexpressed in human malignancies and emerged as a promising drug target. In this study, we verified the inhibitory effect of bergenin on colorectal cancer cells both in vivo and in vitro. In an in vitro setting, bergenin significantly reduced the viability and colony formation and promoted apoptosis of CRC cells dose-dependently. Bergenin decreased the activity of Akt/GSK3β signaling and enhanced the interaction between FBW7 and Mcl-1, which eventually induced Mcl-1 ubiquitination and degradation. Using the HA-Ub K48R mutant, we demonstrated that bergenin promotes Mcl-1 K48-linked polyubiquitination and degradation. In vivo studies showed that bergenin significantly reduced tumor size and weight without toxicity to vital organs in mice. Overall, our results support the role of bergenin in inhibiting CRC cells via inducing Mcl-1 destruction, suggesting that targeting Mcl-1 ubiquitination could be an alternative strategy for antitumor therapy. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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18 pages, 13989 KiB

Open AccessArticle

Regulatory Mechanism on Anti-Glycolytic and Anti-Metastatic Activities Induced by Strobilanthes crispus in Breast Cancer, In Vitro

by Siti Nur Hasyila Muhammad, Nur Arnida Mohd Safuwan, Nik Soriani Yaacob and Agustine Nengsih Fauzi

Pharmaceuticals 2023, 16(2), 153; https://doi.org/10.3390/ph16020153 - 20 Jan 2023

Cited by 3 | Viewed by 2291

Abstract

An active fraction of S. crispus, F3, and its bioactive compounds (lutein, β-sitosterol, and stigmasterol) were reported to have anti-glycolytic activities in MDA-MB-231 cells. Since glycolysis can also regulate metastatic activities in cancer cells, this study investigated the mechanism underlying the anti-glycolytic [...] Read more.

An active fraction of S. crispus, F3, and its bioactive compounds (lutein, β-sitosterol, and stigmasterol) were reported to have anti-glycolytic activities in MDA-MB-231 cells. Since glycolysis can also regulate metastatic activities in cancer cells, this study investigated the mechanism underlying the anti-glycolytic and anti-metastatic activities induced by F3 and its bioactive compounds on MDA-MB-231 cells. The cells were treated with IC₅₀ concentrations of F3, lutein, β-sitosterol, and stigmasterol. GLUT1 protein expression and localization were then observed using a fluorescence microscope. We found that F3, lutein, and β-sitosterol inhibit localization of GLUT1 to the cell membrane, which causes the decrease in glucose uptake. This is supported by a reduction in PKC activity, measured using a spectrophotometer, and increased TXNIP protein expression detected by Western blotting. Both TXNIP and PKC are involved in GLUT1 activation and localization. The expression of signaling proteins involved in the PI3K/AKT pathway was also measured using a flow cytometer. Results show that F3, lutein, β-sitosterol, and stigmasterol reduced the expression of AKT, pAKT, mTOR, and HIF1α in MDA-MB-231 cells. Transwell migration assay was used to measure migration of the MDA-MB-231 cells. A reduction in fibronectin protein expression was observed by fluorescence microscopy, after treatments with F3 and its bioactive compounds, leading to a reduction in the MDA-MB-231 cells’ migratory abilities. As a conclusion, F3 acts as a metabolic inhibitor by inhibiting metabolic rewiring in the promotion of cancer metastasis, potentially due to the presence of its bioactive compounds. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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11 pages, 2330 KiB

Open AccessArticle

MAPK Cascade Signaling Is Involved in α-MMC Induced Growth Inhibition of Multiple Myeloma MM.1S Cells via G2 Arrest and Mitochondrial-Pathway-Dependent Apoptosis In Vitro

by Zi-Wei Cai, Ting Ye, Pei-Wen Jiang, Yu-Jiao Liao, Lin Wang, Qing-Liang Zhang, Wen-Qian Du, Min Huang, Ping Yang and Min-Hui Li

Pharmaceuticals 2023, 16(1), 124; https://doi.org/10.3390/ph16010124 - 13 Jan 2023

Cited by 1 | Viewed by 2303

Abstract

Multiple myeloma is a hematological malignancy characterized by the unrestricted proliferation of plasma cells that secrete monoclonal immunoglobulins in the bone marrow. Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein extracted from the seeds of the edible plant Momordica charantia L., which has [...] Read more.

Multiple myeloma is a hematological malignancy characterized by the unrestricted proliferation of plasma cells that secrete monoclonal immunoglobulins in the bone marrow. Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein extracted from the seeds of the edible plant Momordica charantia L., which has a variety of biological activities. This study aimed to investigate the inhibitory effect of α-MMC on the proliferation of multiple myeloma MM.1S cells and the molecular mechanism of MM.1S cell death induced through the activation of cell signal transduction pathways. The cell counting kit-8 (CCK-8) assay was used to determine the inhibitory effect of α-MMC on the proliferation of MM.1S cells and its toxic effect on normal human peripheral blood mononuclear cells (PBMCs). The effect of α-MMC on the MM.1S cells’ morphology was observed via inverted microscope imaging. The effects of α-MMC on the MM.1S cell cycle, mitochondrial membrane potential (MMP), and apoptosis were explored using propidium iodide, JC-1, annexin V- fluorescein isothiocyanate/propidium iodide fluorescence staining, and flow cytometry (FCM) analysis. Western blot was used to detect the expressions levels of apoptosis-related proteins and MAPK-signaling-pathway-related proteins in MM.1S cells induced by α-MMC. The results of the CCK-8 showed that in the concentration range of no significant toxicity to PBMCs, α-MMC inhibited the proliferation of MM.1S cells in a time-dependent and concentration-dependent manner, and the IC₅₀ value was 13.04 and 7.518 μg/mL for 24 and 48 h, respectively. Through inverted microscope imaging, it was observed that α-MMC induced a typical apoptotic morphology in MM.1S cells. The results of the FCM detection and analysis showed that α-MMC could arrest the MM.1S cells cycle at the G2 phase, decrease the MMP, and induce cell apoptosis. Western blot analysis found that α-MMC upregulated the expression levels of Bax, Bid, cleaved caspase-3, and cleaved PARP, and downregulated the expression levels of Mcl-1. At the same time, α-MMC decreased the expression levels of p-c-Raf, p-MEK1/2, p-ERK1/2, p-MSK1, and p-P90RSK, and increased the expression levels of p-p38, p-SPAK/JNK, p-c-Jun, and p-ATF2. The above results suggest that α-MMC can inhibit the proliferation of multiple myeloma MM.1S cells. MAPK cascade signaling is involved in the growth inhibition effect of α-MMC on MM.1S cells via cycle arrest and mitochondrial-pathway-dependent apoptosis. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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21 pages, 4920 KiB

Open AccessArticle

Piperine Reduces Neoplastic Progression in Cervical Cancer Cells by Downregulating the Cyclooxygenase 2 Pathway

by Luana Pereira Cardoso, Stefanie Oliveira de Sousa, Juliana Prado Gusson-Zanetoni, Laura Luciana de Melo Moreira Silva, Barbara Maria Frigieri, Tiago Henrique, Eloiza Helena Tajara, Sonia Maria Oliani and Flávia Cristina Rodrigues-Lisoni

Pharmaceuticals 2023, 16(1), 103; https://doi.org/10.3390/ph16010103 - 10 Jan 2023

Cited by 15 | Viewed by 2519

Abstract

Cervical cancer is the fourth-most common type of cancer in the world that causes death in women. It is mainly caused by persistent infection by human papillomavirus (HPV) that triggers a chronic inflammatory process. Therefore, the use of anti-inflammatory drugs is a potential [...] Read more.

Cervical cancer is the fourth-most common type of cancer in the world that causes death in women. It is mainly caused by persistent infection by human papillomavirus (HPV) that triggers a chronic inflammatory process. Therefore, the use of anti-inflammatory drugs is a potential treatment option. The effects of piperine, an amino alkaloid derived from Piper nigrum, are poorly understood in cervical cancer inflammation, making it a target of research. This work aimed to investigate the antitumor effect of piperine on cervical cancer and to determine whether this effect is modulated by the cyclooxygenase 2 (PTGS2) pathway using in vitro model of cervical cancer (HeLa, SiHa, CaSki), and non-tumoral (HaCaT) cell lines. The results showed that piperine reduces in vitro parameters associated with neoplastic evolution such as proliferation, viability and migration by cell cycle arrest in the G1/G0 and G2/M phases, with subsequent induction of apoptosis. This action was modulated by downregulation of cyclooxygenase 2 (PTGS2) pathway, which in turn regulates the secretion of cytokines and the expression of mitogen-activated protein kinases (MAPKs), metalloproteinases (MMPs), and their antagonists (TIMPs). These findings indicate the phytotherapeutic potential of piperine as complementary treatment in cervical cancer. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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21 pages, 6230 KiB

Open AccessArticle

Momordica cochinchinensis (Gấc) Seed Extracts Induce Apoptosis and Necrosis in Melanoma Cells

by Dao Nguyen, Jessica Holien, Chaitali Dekiwadia, Thilini Thrimawithana, Terrence Piva and Tien Huynh

Pharmaceuticals 2023, 16(1), 100; https://doi.org/10.3390/ph16010100 - 9 Jan 2023

Cited by 4 | Viewed by 3047

Abstract

Momordica cochinchinensis is a herbal medicine used throughout Asia and this study investigated the antimelanoma potentials and molecular mechanisms of M. cochinchinensis seed with emphasis on extraction to optimise bioactivity. Overall, the aqueous extract was superior, with a wider diversity and higher concentration [...] Read more.

Momordica cochinchinensis is a herbal medicine used throughout Asia and this study investigated the antimelanoma potentials and molecular mechanisms of M. cochinchinensis seed with emphasis on extraction to optimise bioactivity. Overall, the aqueous extract was superior, with a wider diversity and higher concentration of proteins and peptides that was more cytotoxic to the melanoma cells than other extraction solvents. The IC50 of the aqueous extract on melanoma cells were similar to treatment with current anticancer drugs, vemurafenib and cisplatin. This cytotoxicity was cancer-specific with lower cytotoxic effects on HaCaT epidermal keratinocytes. Cytotoxicity correlated with MAPK signalling pathways leading to apoptosis and necrosis induced by triggering tumour necrosis factor receptor-1 (TNFR1), reducing the expression of nuclear factor kappa B (NF-kB), and suppression of BRAF/MEK. This efficacy of M. cochinchinensis seed extracts on melanoma cells provides a platform for future clinical trials as potent adjunctive therapy for metastatic melanoma. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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23 pages, 3730 KiB

Open AccessArticle

Immunomodulatory, Anticancer, and Antimicrobial Effects of Rice Bran Grown in Iraq: An In Vitro and In Vivo Study

by Wamidh H. Talib, Asma Ismail Mahmod, Dima Awajan, Reem Ali Hamed and Intisar Hadi Al-Yasari

Pharmaceuticals 2022, 15(12), 1502; https://doi.org/10.3390/ph15121502 - 1 Dec 2022

Cited by 4 | Viewed by 3006

Abstract

Emerging evidence supports the role of rice bran in cancer prevention. Studies were conducted on multiple rice cultivars. However, limited studies were conducted on rice cultivars in the Middle East. In this study, rice bran growing in Iraq (O. sativa ssp. Japonica, [...] Read more.

Emerging evidence supports the role of rice bran in cancer prevention. Studies were conducted on multiple rice cultivars. However, limited studies were conducted on rice cultivars in the Middle East. In this study, rice bran growing in Iraq (O. sativa ssp. Japonica, cultivars: Amber Barka) was evaluated for its effect on preventing cancer and stimulating the immune system. Rice bran was collected from local mills in Al-Najaf (south of Iraq). Several solvent extracts (ethanol, methanol, n-hexane, and water) were prepared by maceration. MTT assay was used to measure the antiproliferative effects of extracts against a panel of cancer cell lines. The ability of each extract to induce apoptosis and inhibit angiogenesis was measured using standard ELISA kits. The effect of extracts on the immune system was evaluated using a lymphocyte proliferation assay, a pinocytic activity assay, a phagocytic activity assay, and a Th1/Th2 cytokine detection kit. A microbroth dilution method was used to detect the antimicrobial activity of each extract against different microbial strains. LC–MS analysis was used to detect the phytochemical composition of extracts, while DPPH assay was used to determine the antioxidant activity. For the in vivo study, rice bran was added to mouse fodder at 10% and 20%. Mice were treated for two weeks using mouse fodder supplemented with rice bran. In the third week of the experiment, EMT6/P breast cancer cells (1 × 10⁶ cells/mL) were injected subcutaneously into the abdominal area of each mouse. The dimensions of the grown tumors were measured after 14 days of tumor inoculation. A microbroth dilution method was used to evaluate the antimicrobial activity of rice bran extracts against three bacterial strains. The highest antiproliferative activity was observed in ethanol and n-hexane extracts. Ethanol and methanol extract showed the highest activity to induce apoptosis and inhibit angiogenesis. Both extracts were also effective to enhance immunity by activating lymphocytes and phagocytes proliferation with modulations of cytokine levels. The incorporation of rice bran in mice food caused a 20% regression in tumor development and growth compared with the negative control. All extracts exhibited limited antimicrobial activity against tested microorganisms. Methanol extract showed antioxidant activity with an IC₅₀ value of 114 µg/mL. LC–MS analysis revealed the presence of multiple phytochemicals in rice bran including apiin, ferulic acid, and succinic acid. Rice bran is a rich source of active phytochemicals that may inhibit cancer and stimulate the immune system. Rice bran’s biological activities could be due to the presence of multiple synergistically active phytochemicals. Further studies are needed to understand the exact mechanisms of action of rice bran. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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24 pages, 2496 KiB

Open AccessArticle

Antiproliferative Activity of Buddleja saligna (Willd.) against Melanoma and In Vivo Modulation of Angiogenesis

by Danielle Twilley, Velaphi C. Thipe, Navneet Kishore, Pierce Bloebaum, Catarina Roma-Rodrigues, Pedro V. Baptista, Alexandra R. Fernandes, Mamoalosi A. Selepe, Lenka Langhansova, Kattesh Katti and Namrita Lall

Pharmaceuticals 2022, 15(12), 1497; https://doi.org/10.3390/ph15121497 - 30 Nov 2022

Cited by 4 | Viewed by 2297

Abstract

Melanoma cells secrete pro-angiogenic factors, which stimulates growth, proliferation and metastasis, and therefore are key therapeutic targets. Buddleja saligna (BS), and an isolated triterpenoid mixture (DT-BS-01) showed a fifty percent inhibitory concentration (IC₅₀) of 33.80 ± 1.02 and 5.45 ± 0.19 [...] Read more.

Melanoma cells secrete pro-angiogenic factors, which stimulates growth, proliferation and metastasis, and therefore are key therapeutic targets. Buddleja saligna (BS), and an isolated triterpenoid mixture (DT-BS-01) showed a fifty percent inhibitory concentration (IC₅₀) of 33.80 ± 1.02 and 5.45 ± 0.19 µg/mL, respectively, against melanoma cells (UCT-MEL-1) with selectivity index (SI) values of 1.64 and 5.06 compared to keratinocytes (HaCat). Cyclooxygenase-2 (COX-2) inhibition was observed with IC₅₀ values of 35.06 ± 2.96 (BS) and 26.40 ± 4.19 µg/mL (DT-BS-01). BS (30 µg/mL) significantly inhibited interleukin (IL)-6 (83.26 ± 17.60%) and IL-8 (100 ± 0.2%) production, whereas DT-BS-01 (5 µg/mL) showed 51.07 ± 2.83 (IL-6) and 0 ± 6.7% (IL-8) inhibition. Significant vascular endothelial growth factor (VEGF) inhibition, by 15.84 ± 4.54 and 12.21 ± 3.48%, respectively, was observed. In the ex ovo chick embryo yolk sac membrane assay (YSM), BS (15 µg/egg) significantly reduced new blood vessel formation, with 53.34 ± 11.64% newly formed vessels. Silver and palladium BS nanoparticles displayed noteworthy SI values. This is the first report on the significant anti-angiogenic activity of BS and DT-BS-01 and should be considered for preclinical trials as there are currently no US Food and Drug Administration (FDA) approved drugs to inhibit angiogenesis in melanoma. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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16 pages, 3814 KiB

Open AccessArticle

In Vitro Investigation of the Anticancer Properties of Ammodaucus Leucotrichus Coss. & Dur.

by Monia Lenzi, Eleonora Turrini, Elena Catanzaro, Veronica Cocchi, Alessandra Guerrini, Patrizia Hrelia, Sofia Gasperini, Claudio Stefanelli, Mohamed Lamin Abdi Bellau, Valentina Pellicioni, Massimo Tacchini, Giulia Greco and Carmela Fimognari

Pharmaceuticals 2022, 15(12), 1491; https://doi.org/10.3390/ph15121491 - 30 Nov 2022

Cited by 8 | Viewed by 1792

Abstract

Little is known about the pharmacological activity of Ammodaucus leucotrichus Coss. & Dur., a small annual species that grows in the Saharan and sub-Saharan countries. In the present study, we investigated whether the standardized ethanolic extract of A. leucotrichus fruits and R-perillaldehyde, a [...] Read more.

Little is known about the pharmacological activity of Ammodaucus leucotrichus Coss. & Dur., a small annual species that grows in the Saharan and sub-Saharan countries. In the present study, we investigated whether the standardized ethanolic extract of A. leucotrichus fruits and R-perillaldehyde, a monoterpenoid isolated from A. leucotrichus fruits, are able to affect different processes involved in different phases of cancer development. In particular, we explored their genoprotective, proapoptotic, antiproliferative, and cytodifferentiating potential on different human cell models. We analyzed the genoprotective and proapoptotic activity on human lymphoblast cells (TK6) using the micronucleus test, and the cytodifferentiation effects on human promyelocytic cells (HL60) through the evaluation of different markers of differentiation forward granulocytes or monocytes. The results showed that the extract and perillaldehyde were able to induce apoptosis and protect from clastogen-induced DNA damage. To our best knowledge, this is the first report on the ability of A. leucotrichus and perillaldehyde to induce apoptosis and protect DNA from the toxicity of different compounds. Data reported in this work are the starting point for their pharmacological use. Going forward, efforts to determine their effects on other events associated with cancer development, such as angiogenesis and metastasization, will provide important information and improve our understanding of their potential in cancer therapy. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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12 pages, 1632 KiB

Open AccessArticle

Effects of Myristicin in Association with Chemotherapies on the Reversal of the Multidrug Resistance (MDR) Mechanism in Cancer

by Elisa Frederico Seneme, Daiane Carla dos Santos, Carolina Afonso de Lima, Ícaro Augusto Maccari Zelioli, Juliana Mozer Sciani and Giovanna Barbarini Longato

Pharmaceuticals 2022, 15(10), 1233; https://doi.org/10.3390/ph15101233 - 7 Oct 2022

Cited by 8 | Viewed by 2835

Abstract

A range of drugs used in cancer treatment comes from natural sources. However, chemotherapy has been facing a major challenge related to multidrug resistance (MDR), a mechanism that results in a decrease in the intracellular concentration of chemotherapeutic agents, resulting in reduced treatment [...] Read more.

A range of drugs used in cancer treatment comes from natural sources. However, chemotherapy has been facing a major challenge related to multidrug resistance (MDR), a mechanism that results in a decrease in the intracellular concentration of chemotherapeutic agents, resulting in reduced treatment efficacy. The protein most frequently related to this effect is P-glycoprotein (P-gp), which is responsible for promoting drug efflux into the extracellular environment. Myristicin is a natural compound isolated from nutmeg and has antiproliferative activity, which has been reported in the literature. The present study aimed to evaluate the effect of the association between myristicin and chemotherapeutic agents on the NCI/ADR-RES ovarian tumor lineage that presents a phenotype of multidrug resistance by overexpression of P-gp. It was observed that myristicin showed no cytotoxic activity for this cell line, since its IC50 was >1 mM. When myristicin was associated with the chemotherapeutic agents cisplatin and docetaxel, it potentiated their cytotoxic effects, a result evidenced by the decrease in their IC50 of 32.88% and 75.46%, respectively. Studies conducted in silico indicated that myristicin is able to bind and block the main protein responsible for MDR, P-glycoprotein. In addition, the molecule fits five of the pharmacokinetic parameters established by Lipinski, indicating good membrane permeability and bioavailability. Our hypothesis is that, by blocking the extrusion of chemotherapeutic agents, it allows these agents to freely enter cells and perform their functions, stopping the cell cycle. Considering the great impasse in the chemotherapeutic treatment of cancer that is the MDR acquired by tumor cells, investigating effective targets to circumvent this resistance remains a major challenge that needs to be addressed. Therefore, this study encourages further investigation of myristicin as a potential reverser of MDR. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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25 pages, 2202 KiB

Open AccessArticle

LC–MS/MS Phytochemical Profiling, Antioxidant Activity, and Cytotoxicity of the Ethanolic Extract of Atriplex halimus L. against Breast Cancer Cell Lines: Computational Studies and Experimental Validation

by Amine Elbouzidi, Hayat Ouassou, Marouane Aherkou, Loubna Kharchoufa, Nada Meskali, Abdellah Baraich, Hamza Mechchate, Mohamed Bouhrim, Abderrazak Idir, Christophe Hano, Hassan Zrouri and Mohamed Addi

Pharmaceuticals 2022, 15(9), 1156; https://doi.org/10.3390/ph15091156 - 16 Sep 2022

Cited by 39 | Viewed by 5371

Abstract

Atriplex halimus L., also known as Mediterranean saltbush, and locally as “Lgtef”, an halophytic shrub, is used extensively to treat a wide variety of ailments in Morocco. The present study was undertaken to determine the antioxidant activity and cytotoxicity of the ethanolic extract [...] Read more.

Atriplex halimus L., also known as Mediterranean saltbush, and locally as “Lgtef”, an halophytic shrub, is used extensively to treat a wide variety of ailments in Morocco. The present study was undertaken to determine the antioxidant activity and cytotoxicity of the ethanolic extract of A. halimus leaves (AHEE). We first determined the phytochemical composition of AHEE using a liquid chromatography (LC)–tandem mass spectrometry (MS/MS) technique. The antioxidant activity was evaluated using different methods including DPPH scavenging capacity, β-carotene bleaching assay, ABTS scavenging, iron chelation, and the total antioxidant capacity assays. Cytotoxicity was investigated against human cancer breast cells lines MCF-7 and MDA-MB-231. The results showed that the components of the extract are composed of phenolic acids and flavonoids. The DPPH test showed strong scavenging capacity for the leaf extract (IC₅₀ of 0.36 ± 0.05 mg/mL) in comparison to ascorbic acid (IC₅₀ of 0.19 ± 0.02 mg/mL). The β-carotene test determined an IC₅₀ of 2.91 ± 0.14 mg/mL. The IC₅₀ values of ABTS, iron chelation, and TAC tests were 44.10 ± 2.92 TE µmol/mL, 27.40 ± 1.46 mg/mL, and 124 ± 1.27 µg AAE/mg, respectively. In vitro, the AHE extract showed significant inhibitory activity in all tested tumor cell lines, and the inhibition activity was found in a dose-dependent manner. Furthermore, computational techniques such as molecular docking and ADMET analysis were used in this work. Moreover, the physicochemical parameters related to the compounds’ pharmacokinetic indicators were evaluated, including absorption, distribution, metabolism, excretion, and toxicity prediction (Pro-Tox II). Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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14 pages, 1548 KiB

Open AccessArticle

Thymoquinone Inhibits JAK/STAT and PI3K/Akt/ mTOR Signaling Pathways in MV4-11 and K562 Myeloid Leukemia Cells

by Futoon Abedrabbu Al-Rawashde, Abdullah Saleh Al-wajeeh, Mansoureh Nazari Vishkaei, Hanan Kamel M. Saad, Muhammad Farid Johan, Wan Rohani Wan Taib, Imilia Ismail and Hamid Ali Nagi Al-Jamal

Pharmaceuticals 2022, 15(9), 1123; https://doi.org/10.3390/ph15091123 - 8 Sep 2022

Cited by 7 | Viewed by 2981

Abstract

Constitutive activation of Janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT) and Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways plays a crucial role in the development of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Thymoquinone (TQ), one of the [...] Read more.

Constitutive activation of Janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT) and Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways plays a crucial role in the development of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Thymoquinone (TQ), one of the main constituents of Nigella sativa, has shown anti-cancer activities in several cancers. However, the inhibitory effect mechanism of TQ on leukemia has not been fully understood. Therefore, this study aimed to investigate the effect of TQ on JAK/STAT and PI3K/Akt/mTOR pathways in MV4-11 AML cells and K562 CML cells. FLT3-ITD positive MV4-11 cells and BCR-ABL positive K562 cells were treated with TQ. Cytotoxicity assay was assessed using WSTs-8 kit. The expression of the target genes was evaluated using RT-qPCR. The phosphorylation status and the levels of proteins involved in JAK/STAT and PI3K/Akt/mTOR pathways were investigated using Jess western analysis. TQ induced a dose and time dependent inhibition of K562 cells proliferation. TQ significantly downregulated PI3K, Akt, and mTOR and upregulated PTEN expression with a significant inhibition of JAK/STAT and PI3K/Akt/mTOR signaling. In conclusion, TQ reduces the expression of PI3K, Akt, and mTOR genes and enhances the expression of PTEN gene at the mRNA and protein levels. TQ also inhibits JAK/STAT and PI3K/Akt/mTOR pathways, and consequently inhibits proliferation of myeloid leukemia cells, suggesting that TQ has potential anti-leukemic effects on both AML and CML cells. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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Review

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31 pages, 943 KiB

Open AccessReview

The Antitumor Activity of Piplartine: A Review

by Allana Brunna S. Duarte, Rebeca C. Gomes, Vitória Regina V. Nunes, Juan Carlos R. Gonçalves, Camylla A. Correia, Ana Zulmira G. dos Santos and Damião P. de Sousa

Pharmaceuticals 2023, 16(9), 1246; https://doi.org/10.3390/ph16091246 - 4 Sep 2023

Cited by 2 | Viewed by 1461

Abstract

Cancer is a worldwide health problem with high mortality in children and adults, making searching for novel bioactive compounds with potential use in cancer treatment essential. Piplartine, also known as piperlongumine, is an alkamide isolated from Piper longum Linn, with relevant therapeutic potential. [...] Read more.

Cancer is a worldwide health problem with high mortality in children and adults, making searching for novel bioactive compounds with potential use in cancer treatment essential. Piplartine, also known as piperlongumine, is an alkamide isolated from Piper longum Linn, with relevant therapeutic potential. Therefore, this review covered research on the antitumor activity of piplartine, and the studies reported herein confirm the antitumor properties of piplartine and highlight its possible application as an anticancer agent against various types of tumors. The evidence found serves as a reference for advancing mechanistic research on this metabolite and preparing synthetic derivatives or analogs with better antitumor activity in order to develop new drug candidates. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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26 pages, 2186 KiB

Open AccessReview

Cannabidiol-Loaded Nanocarriers and Their Therapeutic Applications

by Elham Assadpour, Atefe Rezaei, Sabya Sachi Das, Balaga Venkata Krishna Rao, Sandeep Kumar Singh, Mohammad Saeed Kharazmi, Niraj Kumar Jha, Saurabh Kumar Jha, Miguel A. Prieto and Seid Mahdi Jafari

Pharmaceuticals 2023, 16(4), 487; https://doi.org/10.3390/ph16040487 - 24 Mar 2023

Cited by 15 | Viewed by 4755

Abstract

Cannabidiol (CBD), one of the most promising constituents isolated from Cannabis sativa, exhibits diverse pharmacological actions. However, the applications of CBD are restricted mainly due to its poor oral bioavailability. Therefore, researchers are focusing on the development of novel strategies for the [...] Read more.

Cannabidiol (CBD), one of the most promising constituents isolated from Cannabis sativa, exhibits diverse pharmacological actions. However, the applications of CBD are restricted mainly due to its poor oral bioavailability. Therefore, researchers are focusing on the development of novel strategies for the effective delivery of CBD with improved oral bioavailability. In this context, researchers have designed nanocarriers to overcome limitations associated with CBD. The CBD-loaded nanocarriers assist in improving the therapeutic efficacy, targetability, and controlled biodistribution of CBD with negligible toxicity for treating various disease conditions. In this review, we have summarized and discussed various molecular targets, targeting mechanisms and types of nanocarrier-based delivery systems associated with CBD for the effective management of various disease conditions. This strategic information will help researchers in the establishment of novel nanotechnology interventions for targeting CBD. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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19 pages, 1375 KiB

Open AccessReview

Autophagy Induction by Scutellaria Flavones in Cancer: Recent Advances

by Hardeep Singh Tuli, Sakshi Bhushan, Ajay Kumar, Poonam Aggarwal, Katrin Sak, Seema Ramniwas, Kanupriya Vashishth, Tapan Behl, Rashmi Rana, Shafiul Haque and Miguel A. Prieto

Pharmaceuticals 2023, 16(2), 302; https://doi.org/10.3390/ph16020302 - 15 Feb 2023

Cited by 8 | Viewed by 3460

Abstract

In parallel with a steady rise in cancer incidence worldwide, the scientific community is increasingly focused on finding novel, safer and more efficient modalities for managing this disease. Over the past decades, natural products have been described as a significant source of new [...] Read more.

In parallel with a steady rise in cancer incidence worldwide, the scientific community is increasingly focused on finding novel, safer and more efficient modalities for managing this disease. Over the past decades, natural products have been described as a significant source of new structural leads for novel drug candidates. Scutellaria root is one of the most studied natural products because of its anticancer potential. Besides just describing the cytotoxic properties of plant constituents, their molecular mechanisms of action in different cancer types are equally important. Therefore, this review article focuses on the role of the Scutellaria flavones wogonin, baicalein, baicalin, scutellarein and scutellarin in regulating the autophagic machinery in diverse cancer models, highlighting these molecules as potential lead compounds for the fight against malignant neoplasms. The knowledge that autophagy can function as a dual-edged sword, acting in both a pro- and antitumorigenic manner, further complicates the issue, revealing an amazing property of flavonoids that behave either as anti- or proautophagic agents. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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28 pages, 1880 KiB

Open AccessReview

Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal

by Suneel Kumar, Stephen O. Mathew, Ravindra Prasad Aharwal, Hardeep Singh Tulli, Chakrabhavi Dhananjaya Mohan, Gautam Sethi, Kwang-Seok Ahn, Kassidy Webber, Sardul Singh Sandhu and Anupam Bishayee

Pharmaceuticals 2023, 16(2), 160; https://doi.org/10.3390/ph16020160 - 22 Jan 2023

Cited by 16 | Viewed by 6026

Abstract

Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer [...] Read more.

Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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36 pages, 2150 KiB

Open AccessReview

Phytochemicals as Regulators of Tumor Glycolysis and Hypoxia Signaling Pathways: Evidence from In Vitro Studies

by Ioana-Ecaterina Pralea, Alina-Maria Petrache, Adrian Bogdan Tigu, Diana Gulei, Radu-Cristian Moldovan, Maria Ilieș, Raul Nicoară, Simona-Codruța Hegheș, Alina Uifălean and Cristina-Adela Iuga

Pharmaceuticals 2022, 15(7), 808; https://doi.org/10.3390/ph15070808 - 28 Jun 2022

Cited by 6 | Viewed by 4658

Abstract

The full understanding of the complex nature of cancer still faces many challenges, as cancers arise not as a result of a single target disruption but rather involving successive genetic and epigenetic alterations leading to multiple altered metabolic pathways. In this light, the [...] Read more.

The full understanding of the complex nature of cancer still faces many challenges, as cancers arise not as a result of a single target disruption but rather involving successive genetic and epigenetic alterations leading to multiple altered metabolic pathways. In this light, the need for a multitargeted, safe and effective therapy becomes essential. Substantial experimental evidence upholds the potential of plant-derived compounds to interfere in several important pathways, such as tumor glycolysis and the upstream regulating mechanisms of hypoxia. Herein, we present a comprehensive overview of the natural compounds which demonstrated, in vitro studies, an effective anticancer activity by affecting key regulators of the glycolytic pathway such as glucose transporters, hexokinases, phosphofructokinase, pyruvate kinase or lactate dehydrogenase. Moreover, we assessed how phytochemicals could interfere in HIF-1 synthesis, stabilization, accumulation, and transactivation, emphasizing PI3K/Akt/mTOR and MAPK/ERK pathways as important signaling cascades in HIF-1 activation. Special consideration was given to cell culture-based metabolomics as one of the most sensitive, accurate, and comprising approaches for understanding the response of cancer cell metabolome to phytochemicals. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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Other

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21 pages, 1882 KiB

Open AccessSystematic Review

Chemical Constituents, Anticancer and Anti-Proliferative Potential of Limonium Species: A Systematic Review

by Naiara Cássia Gancedo, Raquel Isolani, Natalia Castelhano de Oliveira, Celso Vataru Nakamura, Daniela Cristina de Medeiros Araújo, Andreia Cristina Conegero Sanches, Fernanda Stumpf Tonin, Fernando Fernandez-Llimos, Danielly Chierrito and João Carlos Palazzo de Mello

Pharmaceuticals 2023, 16(2), 293; https://doi.org/10.3390/ph16020293 - 14 Feb 2023

Cited by 7 | Viewed by 2396

Abstract

Limonium species represent a source of bioactive compounds that have been widely used in folk medicine. This study aimed to synthesize the anticancer and anti-proliferative potential of Limonium species through a systematic review. Searches were performed in the electronic databases PubMed/MEDLINE, Scopus, and [...] Read more.

Limonium species represent a source of bioactive compounds that have been widely used in folk medicine. This study aimed to synthesize the anticancer and anti-proliferative potential of Limonium species through a systematic review. Searches were performed in the electronic databases PubMed/MEDLINE, Scopus, and Scielo and via a manual search. In vivo or in vitro studies that evaluated the anticancer or anti-proliferative effect of at least one Limonium species were included. In total, 942 studies were identified, with 33 articles read in full and 17 studies included for qualitative synthesis. Of these, 14 (82.35%) refer to in vitro assays, one (5.88%) was in vivo, and two (11.76%) were designed as in vitro and in vivo assays. Different extracts and isolated compounds from Limonium species were evaluated through cytotoxic analysis against various cancer cells lines (especially hepatocellular carcinoma—HepG2; n = 7, 41.18%). Limonium tetragonum was the most evaluated species. The possible cellular mechanism involved in the anticancer activity of some Limonium species included the inhibition of enzymatic activities and expression of matrix metalloproteinases (MMPs), which suggested anti-metastatic effects, anti-melanogenic activity, cell proliferation inhibition pathways, and antioxidant and immunomodulatory effects. The results reinforce the potential of Limonium species as a source for the discovery and development of new potential cytotoxic and anticancer agents. However, further studies and improvements in experimental designs are needed to better demonstrate the mechanism of action of all of these compounds. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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