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Dvorska D, Sebova D, Kajo K, Kapinova A, Svajdlenka E, Goga M, Frenak R, Treml J, Mersakova S, Strnadel J, Mazurakova A, Baranova I, Halasova E, Brozmanova M, Biringer K, Kassayova M, Dankova Z, Smejkal K, Hornak S, Mojzis J, Sadlonova V, Brany D, Kello M, Kubatka P. Chemopreventive and therapeutic effects of Hippophae rhamnoides L. fruit peels evaluated in preclinical models of breast carcinoma. Front Pharmacol 2025; 16:1561436. [PMID: 40371330 PMCID: PMC12075410 DOI: 10.3389/fphar.2025.1561436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 04/21/2025] [Indexed: 05/16/2025] Open
Abstract
Background Cancer remains a major global health challenge, necessitating innovative prevention and treatment approaches. Certain plants, adapted to specific environments, may exhibit bioactive properties with potential anticancer applications. Hypothesis Seaberry (Hippophae rhamnoides L.) fruit peels may exert anticancer effects in breast carcinoma (BC) models through the additive or synergistic actions of their unique secondary metabolites. Methods H. rhamnoides fruit peel extracts were analyzed using the LC-DAD-MS and LC-DAD techniques to profile the content of carotenoids and flavonoids, respectively. The preclinical study evaluated seaberry fruit peel extracts in BC models: (1) a syngeneic 4T1 mouse breast adenocarcinoma model (triple-negative), (2) a rat model of chemically induced mammary carcinogenesis, and (3) in vitro studies with MCF-7 (hormone receptor-positive) and MDA-MB-231 (triple-negative) BC cell lines. Results LC-DAD-MS and LC-DAD analyses identified dominant metabolites, including isorhamnetin, quercetin glycosides, kaempferol glycosides, catechin, zeaxanthin, and lutein. In the 4T1 mouse model, seaberry treatment resulted in a significant, dose-dependent reduction in tumor volume (43% and 48% compared to controls) and a decrease in the mitotic activity index. Serum cytokine analysis showed dose-dependent reductions in IL-6, IL-10, and TNF-α. In the rat chemopreventive model, high-dose seaberry improved cancer prognosis by reducing the ratio of poorly differentiated tumors and increasing caspase-3 and Bax expression while decreasing Ki-67 and malondialdehyde levels. Both treatment doses elevated the Bax/Bcl-2 ratio and reduced the expression of cancer stem cell markers CD44, EpCam, and VEGF compared to controls. Epigenetic analyses revealed histone modifications (H4K16ac, H4K20me3) and altered methylation of tumor-suppressor genes (PITX2, RASSF1, PTEN, TIMP3). Microarray analysis (758 miRNAs) identified beneficial changes in nine oncogenic/tumor-suppressive miRNAs, including miR-10a-5p, miR-322-5p, miR-450a-5p, miR-142-5p, miR-148b-3p, miR-1839-3p, miR-18a-5p, miR-1949, and miR-347. In vitro, ethanolic seaberry extract conferred partial resistance to cisplatin-induced cytotoxicity in MCF-7 and MDA-MB-231 cells at IC50 concentrations. Conclusion This study of H. rhamnoides in rodent BC models shows promising data but requires rigorous, long-term validation. Integrating plant-based nutraceuticals into oncology necessitates precise cancer-type profiling and patient stratification for effective personalized treatments.
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Affiliation(s)
- Dana Dvorska
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dominika Sebova
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Oncology Institute, Bratislava, Slovakia
| | - Andrea Kapinova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Emil Svajdlenka
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Michal Goga
- Department of Botany, Institute of Biology and Ecology, Faculty of Science, P. J. Safarik University, Kosice, Slovakia
| | - Richard Frenak
- Department of Botany, Institute of Biology and Ecology, Faculty of Science, P. J. Safarik University, Kosice, Slovakia
| | - Jakub Treml
- Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Sandra Mersakova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Strnadel
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Ivana Baranova
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
- Biobank for Cancer and Rare Diseases, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Erika Halasova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Mariana Brozmanova
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Monika Kassayova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P. J. Safarik University, Kosice, Slovakia
| | - Zuzana Dankova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
- Biobank for Cancer and Rare Diseases, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Slavomir Hornak
- Small Animal Clinic, University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Vladimira Sadlonova
- Department of Microbiology and Immunology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dusan Brany
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Peter Kubatka
- Laboratory of Experimental and Clinical Regenerative Medicine, Small Animal Clinic, University of Veterinary Medicine and Pharmacy, Kosice, Slovakia
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Nizami ZN, Al Azzani M, Khaldi S, Wali AF, Magramane R, Samad SA, Eid AH, Arafat K, Al Dhaheri Y, Attoub S, Iratni R. Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells. Front Pharmacol 2025; 16:1542204. [PMID: 40176890 PMCID: PMC11962434 DOI: 10.3389/fphar.2025.1542204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/24/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction Colorectal cancer is a leading cause of cancer related-death worldwide, and resistance to 5-fluorouracil (5FU, a key component of chemotherapy regimens, is a major clinical concern. We have previously elucidated the effects of Rhus coriaria ethanolic extract (RCE) in triple-negative breast cancer, CRC, and pancreatic cancer cells. Here, we explored the anticancer effects of RCE in parental (HCT-116-WT) and 5FU-resistant HCT-116 (HCT-116-5FU-R) CRC cells. Methods MTT assay was used to assess cell viability. Muse analyzer was used to assess cell viability, cell cycle distribution, and apoptosis. Additionally, colony formation and growth assays and western blots were performed. In vivo effects of RCE were assessed by an in ovo chick embryo tumor growth assay. Results We found that RCE inhibited the viability and colony formation and growth capacities of HCT-116-WT and HCT-116-5FU-R cells. The antiproliferative effects were attributed to DNA damage-mediated impairment of cell cycle at S phase, and induction of Beclin-1-independent autophagy in both cell lines. Mechanistically, inhibition of the mTOR, STAT3 and p38 MAPK pathways was implicated in the latter. Additionally, RCE induced caspase-7-independent apoptosis in HCT-116-WT cells. However, HCT-116-5FU-R cells were resistant to apoptosis through upregulation of survivin, and downregulation of Bax. Using autophagy and proteasome inhibitors, we clarified that autophagy and the proteasome pathway contributed to RCE-mediated cell death in HCT-116-WT and HCT-116-5FU-R cells. Lastly, we confirmed RCE inhibited the growth of both HCT-116-WT and HCT-116-5FU-R xenografts in a chick embryo model. Discussion Collectively, our findings highlight that RCE is a source of phytochemicals that can be used as anticancer agents for 5FU-resistant CRC.
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Affiliation(s)
- Zohra Nausheen Nizami
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Mazoun Al Azzani
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Samah Khaldi
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Adil Farooq Wali
- Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Rym Magramane
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Shamaa Abdul Samad
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Kholoud Arafat
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Yusra Al Dhaheri
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Samir Attoub
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
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Dvorska D, Mazurakova A, Lackova L, Sebova D, Kajo K, Samec M, Brany D, Svajdlenka E, Treml J, Mersakova S, Strnadel J, Adamkov M, Lasabova Z, Biringer K, Mojzis J, Büsselberg D, Smejkal K, Kello M, Kubatka P. Aronia melanocarpa L. fruit peels show anti-cancer effects in preclinical models of breast carcinoma: The perspectives in the chemoprevention and therapy modulation. Front Oncol 2024; 14:1463656. [PMID: 39435289 PMCID: PMC11491292 DOI: 10.3389/fonc.2024.1463656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/17/2024] [Indexed: 10/23/2024] Open
Abstract
Introduction Within oncology research, there is a high effort for new approaches to prevent and treat cancer as a life-threatening disease. Specific plant species that adapt to harsh conditions may possess unique properties that may be utilized in the management of cancer. Hypothesis Chokeberry fruit is rich in secondary metabolites with anti-cancer activities potentially useful in cancer prevention and treatment. Aims of the study and Methods Based on mentioned hypothesis, the main goal of our study was to evaluate the antitumor effects of dietary administered Aronia melanocarpa L. fruit peels (in two concentrations of 0.3 and 3% [w/w]) in the therapeutic syngeneic 4T1 mouse adenocarcinoma model, the chemopreventive model of chemically induced mammary carcinogenesis in rats, a cell antioxidant assay, and robust in vitro analyses using MCF-7 and MDA-MB-231 cancer cells. Results The dominant metabolites in the A. melanocarpa fruit peel extract tested were phenolic derivatives classified as anthocyanins and procyanidins. In a therapeutic model, aronia significantly reduced the volume of 4T1 tumors at both higher and lower doses. In the same tumors, we noted a significant dose-dependent decrease in the mitotic activity index compared to the control. In the chemopreventive model, the expression of Bax was significantly increased by aronia at both doses. Additionally, aronia decreased Bcl-2 and VEGF levels, increasing the Bax/Bcl-2 ratio compared to the control group. The cytoplasmic expression of caspase-3 was significantly enhanced when aronia was administered at a higher dosage, in contrast to both the control group and the aronia group treated with a lower dosage. Furthermore, the higher dosage of aronia exhibited a significant reduction in the expression of the tumor stem cell marker CD133 compared to the control group. In addition, the examination of aronia`s epigenetic impact on tumor tissue through in vivo analyses revealed significant alterations in histone chemical modifications, specifically H3K4m3 and H3K9m3, miRNAs expression (miR155, miR210, and miR34a) and methylation status of tumor suppressor genes (PTEN and TIMP3). In vitro studies utilizing a methanolic extract of A.melanocarpa demonstrated significant anti-cancer properties in the MCF-7 and MDA-MB-231 cell lines. Various analyses, including Resazurin, cell cycle, annexin V/PI, caspase-3/7, Bcl-2, PARP, and mitochondrial membrane potential, were conducted in this regard. Additionally, the aronia extract enhanced the responsiveness to epirubicin in both cancer cell lines. Conclusion This study is the first to analyze the antitumor effect of A. melanocarpa in selected models of experimental breast carcinoma in vivo and in vitro. The utilization of the antitumor effects of aronia in clinical practice is still minimal and requires precise and long-term clinical evaluations. Individualized cancer-type profiling and patient stratification are crucial for effectively implementing plant nutraceuticals within targeted anti-cancer strategies in clinical oncology.
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Affiliation(s)
- Dana Dvorska
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Lenka Lackova
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dominika Sebova
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Oncology Institute, Bratislava, Slovakia
| | - Marek Samec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dusan Brany
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Emil Svajdlenka
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Jakub Treml
- Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Sandra Mersakova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Strnadel
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Marian Adamkov
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
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El Mahi Y, Nizami ZN, Wali AF, Al Neyadi A, Magramane M, Al Azzani M, Arafat K, Attoub S, Eid AH, Iratni R. Rhus coriaria induces autophagic and apoptotic cell death in pancreatic cancer cells. Front Pharmacol 2024; 15:1412565. [PMID: 39139643 PMCID: PMC11319293 DOI: 10.3389/fphar.2024.1412565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 07/10/2024] [Indexed: 08/15/2024] Open
Abstract
Background:Pancreatic cancer is a leading cause of cancer-related mortality worldwide with increasing global incidence. We previously reported the anticancer effect of Rhus coriaria ethanolic extract (RCE) in triple negative breast and colon cancer cells. Herein, we investigated the anticancer effect of RCE on human pancreatic cancer cells. Methods: Cell viability was measured using Cell Titer-Glo and staining of viable and dead cells based on differential permeability to two DNA binding dyes. Cell cycle distribution and annexin V staining was carried out in Muse cell analyzer. Protein level was determined by Western blot. Tumor growth was assessed by in ovo chick embryo chorioallantoic membrane assay. Results: We found that RCE significantly inhibited the viability and colony growth of pancreatic cancer cells (Panc-1, Mia-PaCa-2, S2-013, AsPC-1). The antiproliferative effects of RCE in pancreatic cancer cells (Panc-1 and Mia-PaCa-2) were mediated through induction of G1 cell cycle arrest, Beclin-1-independent autophagy, and apoptosis. RCE activated both the extrinsic and intrinsic pathways of apoptosis and regulated the Bax/Bcl-2 apoptotic switch. Mechanistically, we found that RCE inhibited the AKT/mTOR pathway, downstream of which, inactivation of the cell cycle regulator p70S6K and downregulation of the antiapoptotic protein survivin was observed. Additionally, we found that RCE-induced autophagy preceded apoptosis. Further, we confirmed the anticancer effect of RCE in a chick embryo xenograft model and found that RCE inhibited the growth of pancreatic cancer xenografts without affecting embryo survival. Conclusion: Collectively, our findings demonstrate that Rhus coriaria exerts potent anti-pancreatic cancer activity though cell cycle impairment, autophagy, and apoptosis, and is hence a promising source of anticancer phytochemicals.
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Affiliation(s)
- Yassine El Mahi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Zohra Nausheen Nizami
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Adil Farooq Wali
- Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Aysha Al Neyadi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohamed Magramane
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mazoun Al Azzani
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Kholoud Arafat
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Samir Attoub
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
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Kubatka P, Koklesova L, Mazurakova A, Brockmueller A, Büsselberg D, Kello M, Shakibaei M. Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling. Cancer Metastasis Rev 2024; 43:87-113. [PMID: 37789138 PMCID: PMC11016017 DOI: 10.1007/s10555-023-10134-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/31/2023] [Indexed: 10/05/2023]
Abstract
Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.
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Affiliation(s)
- Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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Kubatka P, Mazurakova A, Koklesova L, Kuruc T, Samec M, Kajo K, Kotorova K, Adamkov M, Smejkal K, Svajdlenka E, Dvorska D, Brany D, Baranovicova E, Sadlonova V, Mojzis J, Kello M. Salvia officinalis L. exerts oncostatic effects in rodent and in vitro models of breast carcinoma. Front Pharmacol 2024; 15:1216199. [PMID: 38464730 PMCID: PMC10921418 DOI: 10.3389/fphar.2024.1216199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 01/25/2024] [Indexed: 03/12/2024] Open
Abstract
Introduction: Based on extensive data from oncology research, the use of phytochemicals or plant-based nutraceuticals is considered an innovative tool for cancer management. This research aimed to analyze the oncostatic properties of Salvia officinalis L. [Lamiaceae; Salviae officinalis herba] using animal and in vitro models of breast carcinoma (BC). Methods: The effects of dietary administered S. officinalis in two concentrations (0.1%/SAL 0.1/and 1%/SAL 1/) were assessed in both syngeneic 4T1 mouse and chemically induced rat models of BC. The histopathological and molecular evaluations of rodent carcinoma specimens were performed after the autopsy. Besides, numerous in vitro analyses using two human cancer cell lines were performed. Results and Conclusion: The dominant metabolites found in S. officinalis propylene glycol extract (SPGE) were representatives of phenolics, specifically rosmarinic, protocatechuic, and salicylic acids. Furthermore, the occurrence of triterpenoids ursolic and oleanolic acid was proved in SPGE. In a mouse model, a non-significant tumor volume decrease after S. officinalis treatment was associated with a significant reduction in the mitotic activity index of 4T1 tumors by 37.5% (SAL 0.1) and 31.5% (SAL 1) vs. controls (set as a blank group with not applied salvia in the diet). In addition, salvia at higher doses significantly decreased necrosis/whole tumor area ratio by 46% when compared to control tumor samples. In a rat chemoprevention study, S. officinalis at a higher dose significantly lengthened the latency of tumors by 8.5 days and significantly improved the high/low-grade carcinomas ratio vs. controls in both doses. Analyses of the mechanisms of anticancer activities of S. officinalis included well-validated prognostic, predictive, and diagnostic biomarkers that are applied in both oncology practice and preclinical investigation. Our assessment in vivo revealed numerous significant changes after a comparison of treated vs. untreated cancer cells. In this regard, we found an overexpression in caspase-3, an increased Bax/Bcl-2 ratio, and a decrease in MDA, ALDH1, and EpCam expression. In addition, salvia reduced TGF-β serum levels in rats (decrease in IL-6 and TNF-α levels were with borderline significance). Evaluation of epigenetic modifications in rat cancer specimens in vivo revealed a decline in the lysine methylations of H3K4m3 and an increase in lysine acetylation in H4K16ac levels in treated groups. Salvia decreased the relative levels of oncogenic miR21 and tumor-suppressive miR145 (miR210, miR22, miR34a, and miR155 were not significantly altered). The methylation of ATM and PTEN promoters was decreased after S. officinalis treatment (PITX2, RASSF1, and TIMP3 promoters were not altered). Analyzing plasma metabolomics profile in tumor-bearing rats, we found reduced levels of ketoacids derived from BCAAs after salvia treatment. In vitro analyses revealed significant anti-cancer effects of SPGE extract in MCF-7 and MDA-MB-231 cell lines (cytotoxicity, caspase-3/-7, Bcl-2, Annexin V/PI, cell cycle, BrdU, and mitochondrial membrane potential). Our study demonstrates the significant chemopreventive and treatment effects of salvia haulm using animal or in vitro BC models.
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Affiliation(s)
- Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Lenka Koklesova
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Tomas Kuruc
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Marek Samec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Karol Kajo
- Department of Pathology, St. Elisabeth Oncology Institute, Bratislava, Slovakia
| | - Klaudia Kotorova
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Marian Adamkov
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Emil Svajdlenka
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Brno, Czechia
| | - Dana Dvorska
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Dusan Brany
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Eva Baranovicova
- Biomedical Centre Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Vladimira Sadlonova
- Department of Microbiology and Immunology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Mojzis
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia
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7
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Mazurakova A, Koklesova L, Csizmár SH, Samec M, Brockmueller A, Šudomová M, Biringer K, Kudela E, Pec M, Samuel SM, Kassayova M, Hassan STS, Smejkal K, Shakibaei M, Büsselberg D, Saso L, Kubatka P, Golubnitschaja O. Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells - A potential contribution to the predictive, preventive, and personalized medicine. J Adv Res 2024; 55:103-118. [PMID: 36871616 PMCID: PMC10770105 DOI: 10.1016/j.jare.2023.02.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. AIM OF REVIEW We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). KEY SCIENTIFIC CONCEPTS OF REVIEW The working hypothesis of the manuscript proposes HIF-1α - the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.
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Affiliation(s)
- Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Sandra Hurta Csizmár
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Marek Samec
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
| | - Miroslava Šudomová
- Museum of Literature in Moravia, Klášter 1, 66461 Rajhrad, Czech Republic
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Monika Kassayova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P. J. Safarik University, 04001 Kosice, Slovakia
| | - Sherif T S Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic
| | - Karel Smejkal
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, 61242 Brno, Czech Republic
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Pettenkoferstr. 11, D-80336 Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University, P.le Aldo Moro 5, 00185, Rome, Italy
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01, Martin, Slovakia.
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127, Bonn, Germany.
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Thepmalee C, Sawasdee N, Jenkham P, Thephinlap C, Khoothiam K, Suwannasom N, Chokchaisiri R, Panya A, Yenchitsomanus PT. Anti-cancer effect of a phytochemical compound - 7R-acetylmelodorinol - against triple-negative breast cancer cells. Biomed Pharmacother 2023; 166:115286. [PMID: 37573655 DOI: 10.1016/j.biopha.2023.115286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/15/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype currently lacking effective treatment options. Consequently, novel and effective drugs or compounds are urgently needed to treat TNBC. Therefore, this study aimed to evaluate the potential of 7R-acetylmelodorinol (7R-AMDL), a phytochemical compound isolated from Xylopia pierrei Hance, a plant found in Thailand, as a novel therapeutic agent for TNBC. MTT and clonogenic assays showed that 7R-AMDL significantly reduced the survival of breast cancer cell lines, with a markedly potent effect on MDA-MB-231 cells. Flow cytometry showed that treating MDA-MB-231 cells with 7R-AMDL at the concentration of dose 8 µM significantly increased early and late apoptosis after 24 and 48 h compared to the control group (p < 0.0001). The highest tested 7R-AMDL dose upregulated the death receptors and their ligands, with extrinsic and intrinsic apoptosis pathways significantly activated via the caspase cascade, compared to the untreated group (p < 0.05). In addition, immunoblots showed decreased BCL2-like 1 (BCL2L1/Bcl-xL) expression (p < 0.0001). Furthermore, wound healing and Transwell assays showed that at a non-cytotoxic dose (≤4 µM), 7R-AMDL significantly inhibited the MDA-MB-231 cell migration and invasion. This reduction in cell migration was associated with decreased matrix metallopeptidase 9 (MMP-9) expression (p < 0.01) and nuclear factor kappa B (NF-κB) activation (p < 0.05). Altogether, 7R-AMDL has anti-cancer effects against TNBC and the potential to be further developed and evaluated for treating this disease.
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Affiliation(s)
- Chutamas Thepmalee
- Unit of Excellence on Research and Development of Cancer Therapy, University of Phayao, Phayao 56000, Thailand; Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand.
| | - Nunghathai Sawasdee
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Phanitaporn Jenkham
- Unit of Excellence on Research and Development of Cancer Therapy, University of Phayao, Phayao 56000, Thailand; Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Chonthida Thephinlap
- Unit of Excellence on Research and Development of Cancer Therapy, University of Phayao, Phayao 56000, Thailand; Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Krissana Khoothiam
- Unit of Excellence on Research and Development of Cancer Therapy, University of Phayao, Phayao 56000, Thailand; Division of Microbiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Nittiya Suwannasom
- Unit of Excellence on Research and Development of Cancer Therapy, University of Phayao, Phayao 56000, Thailand; Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | | | - Aussara Panya
- Cell Engineering for Cancer Therapy Research Group, Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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9
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Baloghová J, Michalková R, Baranová Z, Mojžišová G, Fedáková Z, Mojžiš J. Spice-Derived Phenolic Compounds: Potential for Skin Cancer Prevention and Therapy. Molecules 2023; 28:6251. [PMID: 37687080 PMCID: PMC10489044 DOI: 10.3390/molecules28176251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Skin cancer is a condition characterized by the abnormal growth of skin cells, primarily caused by exposure to ultraviolet (UV) radiation from the sun or artificial sources like tanning beds. Different types of skin cancer include melanoma, basal cell carcinoma, and squamous cell carcinoma. Despite the advancements in targeted therapies, there is still a need for a safer, highly efficient approach to preventing and treating cutaneous malignancies. Spices have a rich history dating back thousands of years and are renowned for their ability to enhance the flavor, taste, and color of food. Derived from various plant parts like seeds, fruits, bark, roots, or flowers, spices are important culinary ingredients. However, their value extends beyond the culinary realm. Some spices contain bioactive compounds, including phenolic compounds, which are known for their significant biological effects. These compounds have attracted attention in scientific research due to their potential health benefits, including their possible role in disease prevention and treatment, such as cancer. This review focuses on examining the potential of spice-derived phenolic compounds as preventive or therapeutic agents for managing skin cancers. By compiling and analyzing the available knowledge, this review aims to provide insights that can guide future research in identifying new anticancer phytochemicals and uncovering additional mechanisms for combating skin cancer.
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Affiliation(s)
- Janette Baloghová
- Department of Dermatovenerology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (J.B.); (Z.B.); (Z.F.)
| | - Radka Michalková
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia;
| | - Zuzana Baranová
- Department of Dermatovenerology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (J.B.); (Z.B.); (Z.F.)
| | - Gabriela Mojžišová
- Center of Clinical and Preclinical Research MEDIPARK, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia;
| | - Zuzana Fedáková
- Department of Dermatovenerology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; (J.B.); (Z.B.); (Z.F.)
| | - Ján Mojžiš
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Kosice, Slovakia;
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Bayala B, Coulibaly LL, Djigma F, Bunay J, Yonli A, Traore L, Baron S, Figueredo G, Simpore J, Lobaccaro JMA. Chemical Composition of Essential Oil of Cymbopogon schoenanthus (L.) Spreng from Burkina Faso, and Effects against Prostate and Cervical Cancer Cell Lines. Molecules 2023; 28:4561. [PMID: 37299034 PMCID: PMC10254514 DOI: 10.3390/molecules28114561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/26/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023] Open
Abstract
The aim of this research was to evaluate the essential oil of Cymbopogon schoenanthus (L.) Spreng. (C. schoenanthus) from Burkina Faso in terms of cytotoxic activity against LNCaP cells, derived from prostate cancer, and HeLa cells, derived from cervical cancer. Antioxidant activities were evaluated in vitro. Essential oil (EO) was extracted by hydrodistillation and analyzed by GC/FID and GC/MS. Thirty-seven compounds were identified, the major compounds being piperitone (49.9%), δ-2-carene (24.02%), elemol (5.79%) and limonene (4.31%). EO exhibited a poor antioxidant activity, as shown by the inhibition of DPPH radicals (IC50 = 1730 ± 80 µg/mL) and ABTS+. (IC50 = 2890 ± 26.9 µg/mL). Conversely, EO decreased the proliferation of LNCaP and HeLa cells with respective IC50 values of 135.53 ± 5.27 µg/mL and 146.17 ± 11 µg/mL. EO also prevented LNCaP cell migration and led to the arrest of their cell cycle in the G2/M phase. Altogether, this work points out for the first time that EO of C. schoenanthus from Burkina Faso could be an effective natural anticancer agent.
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Affiliation(s)
- Bagora Bayala
- Laboratoire de Biologie Moléculaire et de Génétique (LABIOGENE), Département de Biochimie-Microbiologie, Université Joseph KI-ZERBO, Ouagadougou 03 BP 7021, Burkina Faso; (L.L.C.); (F.D.); (L.T.); (J.S.)
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), Ouagadougou 01 BP 216, Burkina Faso;
- Institut Génétique, Reproduction & Développement, UMR CNRS 6293, INSERM U1103, Université Clermont Auvergne, et Centre de Recherche en Nutrition Humaine Auvergne, 28, Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France
- Ecole Normale Supérieure, Koudougou BP 376, Burkina Faso; (J.B.); (S.B.)
| | - Laetizia Liz Coulibaly
- Laboratoire de Biologie Moléculaire et de Génétique (LABIOGENE), Département de Biochimie-Microbiologie, Université Joseph KI-ZERBO, Ouagadougou 03 BP 7021, Burkina Faso; (L.L.C.); (F.D.); (L.T.); (J.S.)
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), Ouagadougou 01 BP 216, Burkina Faso;
| | - Florencia Djigma
- Laboratoire de Biologie Moléculaire et de Génétique (LABIOGENE), Département de Biochimie-Microbiologie, Université Joseph KI-ZERBO, Ouagadougou 03 BP 7021, Burkina Faso; (L.L.C.); (F.D.); (L.T.); (J.S.)
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), Ouagadougou 01 BP 216, Burkina Faso;
| | - Julio Bunay
- Ecole Normale Supérieure, Koudougou BP 376, Burkina Faso; (J.B.); (S.B.)
| | - Albert Yonli
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), Ouagadougou 01 BP 216, Burkina Faso;
| | - Lassina Traore
- Laboratoire de Biologie Moléculaire et de Génétique (LABIOGENE), Département de Biochimie-Microbiologie, Université Joseph KI-ZERBO, Ouagadougou 03 BP 7021, Burkina Faso; (L.L.C.); (F.D.); (L.T.); (J.S.)
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), Ouagadougou 01 BP 216, Burkina Faso;
| | - Silvère Baron
- Ecole Normale Supérieure, Koudougou BP 376, Burkina Faso; (J.B.); (S.B.)
| | - Gilles Figueredo
- LEXVA Analytique, Biopole Clermont-Limagne, F63360 Saint-Beauzire, France;
| | - Jacques Simpore
- Laboratoire de Biologie Moléculaire et de Génétique (LABIOGENE), Département de Biochimie-Microbiologie, Université Joseph KI-ZERBO, Ouagadougou 03 BP 7021, Burkina Faso; (L.L.C.); (F.D.); (L.T.); (J.S.)
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), Ouagadougou 01 BP 216, Burkina Faso;
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11
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Mazurakova A, Koklesova L, Vybohova D, Samec M, Kudela E, Biringer K, Šudomová M, Hassan STS, Kello M, Büsselberg D, Golubnitschaja O, Kubatka P. Therapy-resistant breast cancer in focus: Clinically relevant mitigation by flavonoids targeting cancer stem cells. Front Pharmacol 2023; 14:1160068. [PMID: 37089930 PMCID: PMC10115970 DOI: 10.3389/fphar.2023.1160068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/27/2023] [Indexed: 04/09/2023] Open
Abstract
Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper.
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Affiliation(s)
- Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
- *Correspondence: Peter Kubatka, ; Alena Mazurakova,
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Desanka Vybohova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Marek Samec
- Department of Pathological Physiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Kamil Biringer
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | | | - Sherif T. S. Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Prague, Czechia
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
- *Correspondence: Peter Kubatka, ; Alena Mazurakova,
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Kafoud A, Salahuddin Z, Ibrahim RS, Al-Janahi R, Mazurakova A, Kubatka P, Büsselberg D. Potential Treatment Options for Neuroblastoma with Polyphenols through Anti-Proliferative and Apoptotic Mechanisms. Biomolecules 2023; 13:563. [PMID: 36979499 PMCID: PMC10046851 DOI: 10.3390/biom13030563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/11/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical resection followed by high-dose chemotherapy with autologous stem-cell rescue and radiation treatment. However, those with high-risk NB are susceptible to relapse and the long-term side effects of standard chemotherapy. Polyphenols, including the sub-class of flavonoids, contain more than one aromatic ring with hydroxyl groups. The literature demonstrates their utility in inducing the apoptosis of neuroblastoma cells, mostly in vitro and some in vivo. This review explores the use of various polyphenols outlined in primary studies, underlines the pathways involved in apoptotic activity, and discusses the dosage and delivery of these polyphenols. Primary studies were obtained from multiple databases with search the terms "neuroblastoma", "flavonoid", and "apoptosis". The in vitro studies showed that polyphenols exert an apoptotic effect on several NB cell lines. These polyphenols include apigenin, genistein, didymin, rutin, quercetin, curcumin, resveratrol, butein, bisphenols, and various plant extracts. The mechanisms of the therapeutic effects include calpain-dependent pathways, receptor-mediated apoptosis, and, notably, and most frequently, mitochondrial apoptosis pathways, including the mitochondrial proteins Bax and Bcl-2. Overall, polyphenols demonstrate potency in decreasing NB proliferation and inducing apoptosis, indicating significant potential for further in vivo research.
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Affiliation(s)
- Aisha Kafoud
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Zoya Salahuddin
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Raghad Sabaawi Ibrahim
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Reem Al-Janahi
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Dietrich Büsselberg
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
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Rhus coriaria L. (Sumac), a Versatile and Resourceful Food Spice with Cornucopia of Polyphenols. Molecules 2022; 27:molecules27165179. [PMID: 36014419 PMCID: PMC9414570 DOI: 10.3390/molecules27165179] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/21/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
In recent years, utilization of Rhus coriaria L. (sumac) is upgrading not only in their culinary use and human nutrition, but also in the pharmaceutical industry, food industry and veterinary practices. This is driven by accumulating evidence that support the ethnobotanical use of this plant; in particular, advanced knowledge of the content of nutritional, medicinal and techno-functional bioactive ingredients. Herein, we discuss polyphenolic compounds as the main bioactive ingredients in Rhus coriaria L., which contribute mainly to the significance and utility of this spice. Most of the antioxidant potential and therapeutic roles of sumac are increasingly attributed to its constituent tannins, flavonoids, and phenolic acids. Hydroxyphenyl pyranoanthocyanins and other anthocynins are responsible for the highly desired red pigments accounting for the strong pigmentation capacity and colorant ability of sumac. Certain polyphenols and the essential oil components are responsible for the peculiar flavor and antimicrobial activity of sumac. Tannin-rich sumac extracts and isolates are known to enhance the food quality and the oxidative stability of animal products such as meat and milk. In conclusion, polyphenol-rich sumac extracts and its bioactive ingredients could be exploited towards developing novel food products which do not only address the current consumers' interests regarding organoleptic and nutritional value of food, but also meet the growing need for 'clean label' as well as value addition with respect to antioxidant capacity, disease prevention, and health promotion in humans.
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14
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Zhao X, Ling F, Zhang GW, Yu N, Yang J, Xin XY. The Correlation Between MicroRNAs and Diabetic Retinopathy. Front Immunol 2022; 13:941982. [PMID: 35958584 PMCID: PMC9358975 DOI: 10.3389/fimmu.2022.941982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/23/2022] [Indexed: 11/23/2022] Open
Abstract
Micro ribonucleic acids (miRNAs), as a category of post-transcriptional gene inhibitors, have a wide range of biological functions, are involved in many pathological processes, and are attractive therapeutic targets. Considerable evidence in ophthalmology indicates that miRNAs play an important role in diabetic retinopathy (DR), especially in inflammation, oxidative stress, and neurodegeneration. Targeting specific miRNAs for the treatment of DR has attracted much attention. This is a review focusing on the pathophysiological roles of miRNAs in DR, diabetic macular edema, and proliferative DR complex multifactorial retinal diseases, with particular emphasis on how miRNAs regulate complex molecular pathways and underlying pathomechanisms. Moreover, the future development potential and application limitations of therapy that targets specific miRNAs for DR are discussed.
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Affiliation(s)
- Xin Zhao
- Department of Ophthalmology, Inner Mongolia Baogang Hospita, Baotou, Inner Mongolia, China
| | - Feng Ling
- Department of Ophthalmology, Inner Mongolia Baogang Hospita, Baotou, Inner Mongolia, China
| | - Guang wei Zhang
- Department of Cardiology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China
| | - Na Yu
- Department of Scientific research, Inner Mongolia Baogang Hospita, Baotou, Inner Mongolia, China
| | - Jing Yang
- Department of Biology, Inner Mongolia University of Science and Technology Baotou Medical College, Baotou, Inner Mongolia, China
- *Correspondence: Jing Yang, ; Xiang yang Xin,
| | - Xiang yang Xin
- Department of Ophthalmology, Inner Mongolia Baogang Hospita, Baotou, Inner Mongolia, China
- *Correspondence: Jing Yang, ; Xiang yang Xin,
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Ullah A, Lim SI. Plant Extract-Based Synthesis of Metallic Nanomaterials, Their Applications, and Safety Concerns. Biotechnol Bioeng 2022; 119:2273-2304. [PMID: 35635495 DOI: 10.1002/bit.28148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 04/12/2022] [Accepted: 05/19/2022] [Indexed: 11/06/2022]
Abstract
Nanotechnology has attracted the attention of researchers from different scientific fields because of the escalated properties of nanomaterials compared with the properties of macromolecules. Nanomaterials can be prepared through different approaches involving physical and chemical methods. The development of nanomaterials through plant-based green chemistry approaches is more advantageous than other methods from the perspectives of environmental safety, animal, and human health. The biomolecules and metabolites of plants act as reducing and capping agents for the synthesis of metallic green nanomaterials. Plant-based synthesis is a preferred approach as it is not only cost-effective, easy, safe, clean, and eco-friendly but also provides pure nanomaterials in high yield. Since nanomaterials have antimicrobial and antioxidant potential, green nanomaterials synthesized from plants can be used for a variety of biomedical and environmental remediation applications. Past studies have focused mainly on the overall biogenic synthesis of individual or combinations of metallic nanomaterials and their oxides from different biological sources, including microorganisms and biomolecules. Moreover, from the viewpoint of biomedical applications, the literature is mainly focusing on synthetic nanomaterials. Herein, we discuss the extraction of green molecules and recent developments in the synthesis of different plant-based metallic nanomaterials, including silver, gold, platinum, palladium, copper, zinc, iron, and carbon. Apart from the biomedical applications of metallic nanomaterials, including antimicrobial, anticancer, diagnostic, drug delivery, tissue engineering, and regenerative medicine applications, their environmental remediation potential is also discussed. Furthermore, safety concerns and safety regulations pertaining to green nanomaterials are also discussed. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Aziz Ullah
- Department of Chemical Engineering, Pukyong National University, Busan, 48513, Republic of Korea.,Gomal Centre of Pharmaceutical Sciences, Faculty of Pharmacy, Gomal University Dera Ismail Khan, 29050, Khyber Pakhtunkhwa, Pakistan
| | - Sung In Lim
- Department of Chemical Engineering, Pukyong National University, Busan, 48513, Republic of Korea
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16
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Mazurakova A, Koklesova L, Samec M, Kudela E, Kajo K, Skuciova V, Csizmár SH, Mestanova V, Pec M, Adamkov M, Al-Ishaq RK, Smejkal K, Giordano FA, Büsselberg D, Biringer K, Golubnitschaja O, Kubatka P. Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care. EPMA J 2022; 13:315-334. [PMID: 35437454 PMCID: PMC9008621 DOI: 10.1007/s13167-022-00277-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 03/21/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer incidence is actually the highest one among all cancers. Overall breast cancer management is associated with challenges considering risk assessment and predictive diagnostics, targeted prevention of metastatic disease, appropriate treatment options, and cost-effectiveness of approaches applied. Accumulated research evidence indicates promising anti-cancer effects of phytochemicals protecting cells against malignant transformation, inhibiting carcinogenesis and metastatic spread, supporting immune system and increasing effectiveness of conventional anti-cancer therapies, among others. Molecular and sub-/cellular mechanisms are highly complex affecting several pathways considered potent targets for advanced diagnostics and cost-effective treatments. Demonstrated anti-cancer affects, therefore, are clinically relevant for improving individual outcomes and might be applicable to the primary (protection against initial cancer development), secondary (protection against potential metastatic disease development), and tertiary (towards cascading complications) care. However, a detailed data analysis is essential to adapt treatment algorithms to individuals’ and patients’ needs. Consequently, advanced concepts of patient stratification, predictive diagnostics, targeted prevention, and treatments tailored to the individualized patient profile are instrumental for the cost-effective application of natural anti-cancer substances to improve overall breast cancer management benefiting affected individuals and the society at large.
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17
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Mirzaei S, Gholami MH, Hushmandi K, Hashemi F, Zabolian A, Canadas I, Zarrabi A, Nabavi N, Aref AR, Crea F, Wang Y, Ashrafizadeh M, Kumar AP. The long and short non-coding RNAs modulating EZH2 signaling in cancer. J Hematol Oncol 2022; 15:18. [PMID: 35236381 PMCID: PMC8892735 DOI: 10.1186/s13045-022-01235-1] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are a large family of RNA molecules with no capability in encoding proteins. However, they participate in developmental and biological processes and their abnormal expression affects cancer progression. These RNA molecules can function as upstream mediators of different signaling pathways and enhancer of zeste homolog 2 (EZH2) is among them. Briefly, EZH2 belongs to PRCs family and can exert functional roles in cells due to its methyltransferase activity. EZH2 affects gene expression via inducing H3K27me3. In the present review, our aim is to provide a mechanistic discussion of ncRNAs role in regulating EZH2 expression in different cancers. MiRNAs can dually induce/inhibit EZH2 in cancer cells to affect downstream targets such as Wnt, STAT3 and EMT. Furthermore, miRNAs can regulate therapy response of cancer cells via affecting EZH2 signaling. It is noteworthy that EZH2 can reduce miRNA expression by binding to promoter and exerting its methyltransferase activity. Small-interfering RNA (siRNA) and short-hairpin RNA (shRNA) are synthetic, short ncRNAs capable of reducing EZH2 expression and suppressing cancer progression. LncRNAs mainly regulate EZH2 expression via targeting miRNAs. Furthermore, lncRNAs induce EZH2 by modulating miRNA expression. Circular RNAs (CircRNAs), like lncRNAs, affect EZH2 expression via targeting miRNAs. These areas are discussed in the present review with a focus on molecular pathways leading to clinical translation.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology and Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, 1417466191, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Israel Canadas
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Translational Sciences, Xsphera Biosciences Inc., Boston, MA, USA
| | - Francesco Crea
- Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK
| | - Yuzhuo Wang
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada.
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, 34956, Turkey.
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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18
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Khalil M, Rita Caponio G, Diab F, Shanmugam H, Di Ciaula A, Khalifeh H, Vergani L, Calasso M, De Angelis M, Portincasa P. Unraveling the beneficial effects of herbal Lebanese mixture “Za’atar”. History, studies, and properties of a potential healthy food ingredient. J Funct Foods 2022; 90:104993. [DOI: 10.1016/j.jff.2022.104993] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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19
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Haffez H, Osman S, Ebrahim HY, Hassan ZA. Growth Inhibition and Apoptotic Effect of Pine Extract and Abietic Acid on MCF-7 Breast Cancer Cells via Alteration of Multiple Gene Expressions Using In Vitro Approach. Molecules 2022; 27:293. [PMID: 35011526 PMCID: PMC8746537 DOI: 10.3390/molecules27010293] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/11/2021] [Accepted: 12/22/2021] [Indexed: 01/09/2023] Open
Abstract
In vitro anti-proliferative activity of Pinus palustris extract and its purified abietic acid was assessed against different human cancer cell lines (HepG-2, MCF-7 and HCT-116) compared to normal WI-38 cell line. Abietic acid showed more promising IC50 values against MCF-7 cells than pine extract (0.06 µg/mL and 0.11 µM, respectively), with insignificant cytotoxicity toward normal fibroblast WI-38 cells. Abietic acid triggered both G2/M cell arrest and subG0-G1 subpopulation in MCF-7, compared to SubG0-G1 subpopulation arrest only for the extract. It also induced overexpression of key apoptotic genes (Fas, FasL, Casp3, Casp8, Cyt-C and Bax) and downregulation of both proliferation (VEGF, IGFR1, TGF-β) and oncogenic (C-myc and NF-κB) genes. Additionally, abietic acid induced overexpression of cytochrome-C protein. Furthermore, it increased levels of total antioxidants to diminish carcinogenesis and chemotherapy resistance. P. palustris is a valuable source of active abietic acid, an antiproliferative agent to MCF-7 cells through induction of apoptosis with promising future anticancer agency in breast cancer therapy.
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Affiliation(s)
- Hesham Haffez
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt;
- Helwan Structural Biology Center for Excellence, Helwan University, Cairo 11795, Egypt
| | | | - Hassan Y. Ebrahim
- Pharmacognosy Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt;
| | - Zeinab A. Hassan
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt;
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20
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Shrihastini V, Muthuramalingam P, Adarshan S, Sujitha M, Chen JT, Shin H, Ramesh M. Plant Derived Bioactive Compounds, Their Anti-Cancer Effects and In Silico Approaches as an Alternative Target Treatment Strategy for Breast Cancer: An Updated Overview. Cancers (Basel) 2021; 13:cancers13246222. [PMID: 34944840 PMCID: PMC8699774 DOI: 10.3390/cancers13246222] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer is one of the most common malignant diseases that occur worldwide, among which breast cancer is the second leading cause of death in women. The subtypes are associated with differences in the outcome and were selected for treatments according to the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor. Triple-negative breast cancer, one of the subtypes of breast cancer, is difficult to treat and can even lead to death. If breast cancer is not treated during the initial stages, it may spread to nearby organs, a process called metastasis, through the blood or lymph system. For in vitro studies, MCF-7, MDA-MB-231, MDA-MB-468, and T47B are the most commonly used breast cancer cell lines. Clinically, chemotherapy and radiotherapy are usually expensive and can also cause side effects. To overcome these issues, medicinal plants could be the best alternative for chemotherapeutic drugs with fewer side effects and cost-effectiveness. Furthermore, the genes involved in breast cancer can be regulated and synergized with signaling molecules to suppress the proliferation of breast cancer cells. In addition, nanoparticles encapsulating (nano-encapsulation) medicinal plant extracts showed a significant reduction in the apoptotic and cytotoxic activities of breast cancer cells. This present review mainly speculates an overview of the native medicinal plant derived anti-cancerous compounds with its efficiency, types and pathways involved in breast cancer along with its genes, the mechanism of breast cancer brain metastasis, chemoresistivity and its mechanism, bioinformatics approaches which could be an effective alternative for drug discovery.
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Affiliation(s)
- Vijayakumar Shrihastini
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India; (V.S.); (M.S.)
| | - Pandiyan Muthuramalingam
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India; (V.S.); (M.S.)
- Correspondence: (P.M.); (J.-T.C.)
| | - Sivakumar Adarshan
- Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630003, Tamil Nadu, India; (S.A.); (M.R.)
| | - Mariappan Sujitha
- Department of Biotechnology, Sri Shakthi Institute of Engineering and Technology, Coimbatore 641062, Tamil Nadu, India; (V.S.); (M.S.)
| | - Jen-Tsung Chen
- Department of Life Sciences, National University of Kaohsiung, Kaohsiung 811, Taiwan
- Correspondence: (P.M.); (J.-T.C.)
| | - Hyunsuk Shin
- Department of Horticultural Sciences, Gyeongsang National University, Jinju 52725, Korea;
| | - Manikandan Ramesh
- Department of Biotechnology, Science Campus, Alagappa University, Karaikudi 630003, Tamil Nadu, India; (S.A.); (M.R.)
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21
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Khalil M, Hayek S, Khalil N, Serale N, Vergani L, Calasso M, De Angelis M, Portincasa P. Role of Sumac (Rhus coriaria L.) in the management of metabolic syndrome and related disorders: Focus on NAFLD-atherosclerosis interplay. J Funct Foods 2021; 87:104811. [DOI: 10.1016/j.jff.2021.104811] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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22
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Abstract
The proliferation, metastasis and therapy response of tumour cells are tightly regulated by interaction among various signalling networks. The microRNAs (miRNAs) can bind to 3'-UTR of mRNA and down-regulate expression of target gene. The miRNAs target various molecular pathways in regulating biological events such as apoptosis, differentiation, angiogenesis and migration. The aberrant expression of miRNAs occurs in cancers and they have both tumour-suppressor and tumour-promoting functions. On the contrary, SOX proteins are capable of binding to DNA and regulating gene expression. SOX2 is a well-known member of SOX family that its overexpression in different cancers to ensure progression and stemness. The present review focuses on modulatory impact of miRNAs on SOX2 in affecting growth, migration and therapy response of cancers. The lncRNAs and circRNAs can function as upstream mediators of miRNA/SOX2 axis in cancers. In addition, NF-κB, TNF-α and SOX17 are among other molecular pathways regulating miRNA/SOX2 axis in cancer. Noteworthy, anti-cancer compounds including bufalin and ovatodiolide are suggested to regulate miRNA/SOX2 axis in cancers. The translation of current findings to clinical course can pave the way to effective treatment of cancer patients and improve their prognosis.
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23
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Liskova A, Samec M, Koklesova L, Brockmueller A, Zhai K, Abdellatif B, Siddiqui M, Biringer K, Kudela E, Pec M, Gadanec LK, Šudomová M, Hassan STS, Zulli A, Shakibaei M, Giordano FA, Büsselberg D, Golubnitschaja O, Kubatka P. Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles. EPMA J 2021; 12:155-176. [PMID: 34025826 PMCID: PMC8126506 DOI: 10.1007/s13167-021-00242-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 04/16/2021] [Indexed: 02/07/2023]
Abstract
Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities.
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Affiliation(s)
- Alena Liskova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Marek Samec
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lenka Koklesova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Kevin Zhai
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Basma Abdellatif
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Manaal Siddiqui
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Kamil Biringer
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Erik Kudela
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Martin Pec
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Laura Kate Gadanec
- Institute for Health and Sport, Victoria University, Melbourne, 3030 Australia
| | - Miroslava Šudomová
- Museum of Literature in Moravia, Klášter 1, 66461 Rajhrad, Czech Republic
| | - Sherif T. S. Hassan
- Department of Applied Ecology, Faculty of Environmental Sciences, Czech University of Life Sciences Prague, Kamýcká 129, 16500 Prague, Czech Republic
| | - Anthony Zulli
- Institute for Health and Sport, Victoria University, Melbourne, 3030 Australia
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Dietrich Büsselberg
- Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, 24144 Doha, Qatar
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
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24
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Soleymani L, Zarrabi A, Hashemi F, Hashemi F, Zabolian A, Banihashemi SM, Moghadam SS, Hushmandi K, Samarghandian S, Ashrafizadeh M, Khan H. Role of ZEB family members in proliferation, metastasis and chemoresistance of prostate cancer cells: Revealing signaling networks. Curr Cancer Drug Targets 2021; 21:749-767. [PMID: 34077345 DOI: 10.2174/1568009621666210601114631] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/10/2021] [Accepted: 03/19/2021] [Indexed: 11/22/2022]
Abstract
Prostate cancer (PCa) is one of the leading causes of death worldwide. A variety of strategies including surgery, chemotherapy, radiotherapy and immunotherapy are applied for PCa treatment. PCa cells are responsive towards therapy at early stages, but they can obtain resistance in the advanced stage. Furthermore, their migratory ability is high in advanced stages. It seems that genetic and epigenetic factors play an important in this case. Zinc finger E-box-binding homeobox (ZEB) is a family of transcription with two key members including ZEB1 and ZEB2. ZEB family members are known due to their involvement in promoting cancer metastasis via EMT induction. Recent studies have shown their role in cancer proliferation and inducing therapy resistance. In the current review, we focus on revealing role of ZEB1 and ZEB2 in PCa. ZEB family members that are able to significantly promote proliferation and viability of cancer cells. ZEB1 and ZEB2 enhance migration and invasion of PCa cells via EMT induction. Overexpression of ZEB1 and ZEB2 is associated with poor prognosis of PCa. ZEB1 and ZEB2 upregulation occurs during PCa progression and can provide therapy resistance to cancer cells. PRMT1, Smad2, and non-coding RNAs can function as upstream mediators of the ZEB family. Besides, Bax, Bcl-2, MRP1, N-cadherin and E-cadherin can be considered as downstream targets of ZEB family in PCa.
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Affiliation(s)
- Leyla Soleymani
- Department of biology, school of science, Urmia university, Urmia, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul. Turkey
| | - Farid Hashemi
- Department of Comparative Biosciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shirin Sabouhi Moghadam
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite -Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul. Turkey
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, 23200. Pakistan
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25
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Mirzaei S, Hushmandi K, Zabolian A, Saleki H, Torabi SMR, Ranjbar A, SeyedSaleh S, Sharifzadeh SO, Khan H, Ashrafizadeh M, Zarrabi A, Ahn KS. Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies. Molecules 2021; 26:2382. [PMID: 33921908 PMCID: PMC8073650 DOI: 10.3390/molecules26082382] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran 1477893855, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417466191, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Seyed Mohammad Reza Torabi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Adnan Ranjbar
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - SeyedHesam SeyedSaleh
- Student Research Committee, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Seyed Omid Sharifzadeh
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul 34956, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey
| | - Kwang-Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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26
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Employing siRNA tool and its delivery platforms in suppressing cisplatin resistance: Approaching to a new era of cancer chemotherapy. Life Sci 2021; 277:119430. [PMID: 33789144 DOI: 10.1016/j.lfs.2021.119430] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/10/2021] [Accepted: 03/23/2021] [Indexed: 12/18/2022]
Abstract
Although chemotherapy is a first option in treatment of cancer patients, drug resistance has led to its failure, requiring strategies to overcome it. Cancer cells are capable of switching among molecular pathways to ensure their proliferation and metastasis, leading to their resistance to chemotherapy. The molecular pathways and mechanisms that are responsible for cancer progression and growth, can be negatively affected for providing chemosensitivity. Small interfering RNA (siRNA) is a powerful tool extensively applied in cancer therapy in both pre-clinical (in vitro and in vivo) and clinical studies because of its potential in suppressing tumor-promoting factors. As such oncogene pathways account for cisplatin (CP) resistance, their targeting by siRNA plays an important role in reversing chemoresistance. In the present review, application of siRNA for suppressing CP resistance is discussed. The first priority of using siRNA is sensitizing cancer cells to CP-mediated apoptosis via down-regulating survivin, ATG7, Bcl-2, Bcl-xl, and XIAP. The cancer stem cell properties and related molecular pathways including ID1, Oct-4 and nanog are inhibited by siRNA in CP sensitivity. Cell cycle arrest and enhanced accumulation of CP in cancer cells can be obtained using siRNA. In overcoming siRNA challenges such as off-targeting feature and degradation, carriers including nanoparticles and biological carriers have been applied. These carriers are important in enhancing cellular accumulation of siRNA, elevating gene silencing efficacy and reversing CP resistance.
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Koklesova L, Samec M, Liskova A, Zhai K, Büsselberg D, Giordano FA, Kubatka P, Golunitschaja O. Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine. EPMA J 2021; 12:27-40. [PMID: 33686350 PMCID: PMC7931170 DOI: 10.1007/s13167-021-00237-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023]
Abstract
Mitochondrial injury plays a key role in the aetiopathology of multifactorial diseases exhibiting a "vicious circle" characteristic for pathomechanisms of the mitochondrial and multi-organ damage frequently developed in a reciprocal manner. Although the origin of the damage is common (uncontrolled ROS release, diminished energy production and extensive oxidative stress to life-important biomolecules such as mtDNA and chrDNA), individual outcomes differ significantly representing a spectrum of associated pathologies including but not restricted to neurodegeneration, cardiovascular diseases and cancers. Contextually, the role of predictive, preventive and personalised (PPPM/3P) medicine is to introduce predictive analytical approaches which allow for distinguishing between individual outcomes under circumstance of mitochondrial impairments followed by cost-effective targeted prevention and personalisation of medical services. Current article considers innovative concepts and analytical instruments to advance management of mitochondriopathies and associated pathologies.
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Affiliation(s)
- Lenka Koklesova
- Department of Obstetrics and Gynaecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Marek Samec
- Department of Obstetrics and Gynaecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Alena Liskova
- Department of Obstetrics and Gynaecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, 24144 Qatar
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, 24144 Qatar
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Olga Golunitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
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Liskova A, Samec M, Koklesova L, Kudela E, Kubatka P, Golubnitschaja O. Mitochondriopathies as a Clue to Systemic Disorders-Analytical Tools and Mitigating Measures in Context of Predictive, Preventive, and Personalized (3P) Medicine. Int J Mol Sci 2021; 22:ijms22042007. [PMID: 33670490 PMCID: PMC7922866 DOI: 10.3390/ijms22042007] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/11/2021] [Accepted: 02/14/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a "vicious circle" in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies.
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Affiliation(s)
- Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia; (A.L.); (M.S.); (L.K.); (E.K.)
| | - Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia; (A.L.); (M.S.); (L.K.); (E.K.)
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia; (A.L.); (M.S.); (L.K.); (E.K.)
| | - Erik Kudela
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia; (A.L.); (M.S.); (L.K.); (E.K.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
- European Association for Predictive, Preventive and Personalised Medicine, EPMA, 1160 Brussels, Belgium
- Correspondence: (P.K.); (O.G.)
| | - Olga Golubnitschaja
- European Association for Predictive, Preventive and Personalised Medicine, EPMA, 1160 Brussels, Belgium
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, 53127 Bonn, Germany
- Correspondence: (P.K.); (O.G.)
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Ashrafizadeh M, Gholami MH, Mirzaei S, Zabolian A, Haddadi A, Farahani MV, Kashani SH, Hushmandi K, Najafi M, Zarrabi A, Ahn KS, Khan H. Dual relationship between long non-coding RNAs and STAT3 signaling in different cancers: New insight to proliferation and metastasis. Life Sci 2021; 270:119006. [PMID: 33421521 DOI: 10.1016/j.lfs.2020.119006] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/28/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022]
Abstract
Uncontrolled growth and metastasis of cancer cells is an increasing challenge for overcoming cancer, and improving survival of patients. Complicated signaling networks account for proliferation and invasion of cancer cells that need to be elucidated for providing effective cancer therapy, and minimizing their malignancy. Long non-coding RNAs (lncRNAs) are RNA molecules with a length of more than 200 nucleotides. They participate in cellular events, and their dysregulation in a common phenomenon in different cancers. Noteworthy, lncRNAs can regulate different molecular pathways, and signal transducer and activator of transcription 3 (STAT3) is one of them. STAT3 is a tumor-promoting factors in cancers due to its role in cancer proliferation (cell cycle progression and apoptosis inhibition) and metastasis (EMT induction). LncRNAs can function as upstream mediators of STAT3 pathway, reducing/enhancing its expression. This dual relationship is of importance in affecting proliferation and metastasis of cancer cells. The response of cancer cells to therapy such as chemotherapy and radiotherapy is regulated by lncRNA/STAT3 axis. Tumor-promoting lncRNAs including NEAT1, SNHG3 and H19 induces STAT3 expression, while tumor-suppressing lncRNAs such as MEG3, PTCSC3 and NKILA down-regulate STAT3 expression. Noteworthy, upstream mediators of STAT3 such as microRNAs can be regulated by lncRNAs. These complicated signaling networks are mechanistically described in the current review.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | | | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Haddadi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | | | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran; Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan.
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