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Article ; Online: Perspectives on drug repurposing to overcome cancer multidrug resistance mediated by ABCB1 and ABCG2.

Wu, Chung-Pu / Hsiao, Sung-Han / Wu, Yu-Shan

Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

2023 Volume 71, Page(s) 101011

Abstract: The overexpression of the human ATP-binding cassette (ABC) transporters in cancer cells is a common mechanism involved in developing multidrug resistance (MDR). Unfortunately, there are currently no approved drugs specifically designed to treat multidrug- ...

Abstract	The overexpression of the human ATP-binding cassette (ABC) transporters in cancer cells is a common mechanism involved in developing multidrug resistance (MDR). Unfortunately, there are currently no approved drugs specifically designed to treat multidrug-resistant cancers, making MDR a significant obstacle to successful chemotherapy. Despite over two decades of research, developing transporter-specific inhibitors for clinical use has proven to be a challenging endeavor. As an alternative approach, drug repurposing has gained traction as a more practical method to discover clinically effective modulators of drug transporters. This involves exploring new indications for already-approved drugs, bypassing the lengthy process of developing novel synthetic inhibitors. In this context, we will discuss the mechanisms of ABC drug transporters ABCB1 and ABCG2, their roles in cancer MDR, and the inhibitors that have been evaluated for their potential to reverse MDR mediated by these drug transporters. Our focus will be on providing an up-to-date report on approved drugs tested for their inhibitory activities against these drug efflux pumps. Lastly, we will explore the challenges and prospects of repurposing already approved medications for clinical use to overcome chemoresistance in patients with high tumor expression of ABCB1 and/or ABCG2.
MeSH term(s)	Humans ; Drug Repositioning ; ATP-Binding Cassette Transporters/genetics ; Neoplasms/drug therapy ; Neoplasms/genetics ; Membrane Transport Proteins ; Drug Resistance, Multiple ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; Neoplasm Proteins/genetics ; ATP Binding Cassette Transporter, Subfamily B/genetics
Chemical Substances	ATP-Binding Cassette Transporters ; Membrane Transport Proteins ; ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; ABCB1 protein, human ; ATP Binding Cassette Transporter, Subfamily B
Language	English
Publishing date	2023-10-10
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	1474513-6
ISSN	1532-2084 ; 1368-7646
ISSN (online)	1532-2084
ISSN	1368-7646
DOI	10.1016/j.drup.2023.101011
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Article: Differential Changes in Akt and AMPK Phosphorylation Regulating mTOR Activity in the Placentas of Pregnancies Complicated by Fetal Growth Restriction and Gestational Diabetes Mellitus With Large-For-Gestational Age Infants.

Hung, Tai-Ho / Wu, Chung-Pu / Chen, Szu-Fu

Frontiers in medicine

2021 Volume 8, Page(s) 788969

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2021-12-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2021.788969
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Article ; Online: Differential Changes in Akt and AMPK Phosphorylation Regulating mTOR Activity in the Placentas of Pregnancies Complicated by Fetal Growth Restriction and Gestational Diabetes Mellitus With Large-For-Gestational Age Infants

Tai-Ho Hung / Chung-Pu Wu / Szu-Fu Chen

Frontiers in Medicine, Vol

2021 Volume 8

Abstract: Background: Dysregulation of placental mechanistic target of rapamycin (mTOR) activity has been implicated in the pathophysiology of pregnancies complicated by idiopathic fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) with large- ... ...

Abstract	Background: Dysregulation of placental mechanistic target of rapamycin (mTOR) activity has been implicated in the pathophysiology of pregnancies complicated by idiopathic fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) with large-for-gestational-age (LGA) infants. However, the underlying mechanisms remain unclear.Methods: We obtained placentas from women with normal pregnancies (n = 11) and pregnancies complicated by FGR (n = 12) or GDM with LGA infants (n = 12) to compare the levels of total and phosphorylated forms of Akt, AMPK, TSC2, and mTOR among the three groups and used primary cytotrophoblast cells isolated from 30 normal term placentas to study the effects of oxygen–glucose deprivation (OGD) and increasing glucose concentrations on the changes of these factors in vitro.Results: Placentas from FGR pregnancies had lower phosphorylated Akt (p-Akt) levels (P < 0.05), higher p-AMPKα levels (P < 0.01), and lower mTOR phosphorylation (P < 0.05) compared to that of normal pregnant women. Conversely, women with GDM and LGA infants had higher p-Akt (P < 0.001), lower p-AMPKα (P < 0.05), and higher p-mTOR levels (P < 0.05) in the placentas than normal pregnant women. Furthermore, primary cytotrophoblast cells subjected to OGD had lower p-Akt and p-mTOR (both P < 0.05) and higher p-AMPKα levels (P < 0.05) than those cultured under standard conditions, but increasing glucose concentrations had opposite effects on the respective levels. Administering compound C, an AMPK inhibitor, did not significantly affect Akt phosphorylation but partially reversed mTOR phosphorylation. Administering LY294002, an Akt inhibitor, decreased p-mTOR levels, but did not change the levels of total and phosphorylated AMPKα.Conclusion: These results suggest that Akt and AMPK are involved in the regulation of trophoblast mTOR activity in the placentas of pregnancies complicated by FGR and GDM with LGA infants.
Keywords	placenta ; fetal growth restriction ; gestational diabetes mellitus ; AMP-activated protein kinase ; phosphoinositide 3-kinase ; Akt ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport.

Wu, Chung-Pu / Murakami, Megumi / Li, Yen-Ching / Huang, Yang-Hui / Chang, Yu-Tzu / Hung, Tai-Ho / Wu, Yu-Shan / Ambudkar, Suresh V

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 11

Abstract: The high expression of the ATP-binding cassette (ABC) drug transporter ABCG2 in cancer cells contributes to the emergence of multidrug resistance (MDR) in individuals afflicted with either solid tumors or blood cancers. MDR poses a major impediment in ... ...

Abstract	The high expression of the ATP-binding cassette (ABC) drug transporter ABCG2 in cancer cells contributes to the emergence of multidrug resistance (MDR) in individuals afflicted with either solid tumors or blood cancers. MDR poses a major impediment in the realm of clinical cancer chemotherapy. Recently, substantial endeavors have been dedicated to identifying bioactive compounds isolated from nature capable of counteracting ABCG2-mediated MDR in cancer cells. Imperatorin, a natural coumarin derivative renowned for its diverse pharmacological properties, has not previously been explored for its impact on cancer drug resistance. This study investigates the chemosensitizing potential of imperatorin in ABCG2-overexpressing cancer cells. Experimental results reveal that at sub-toxic concentrations, imperatorin significantly antagonizes the activity of ABCG2 and reverses ABCG2-mediated MDR in a concentration-dependent manner. Furthermore, biochemical data and in silico analysis of imperatorin docking to the inward-open conformation of human ABCG2 indicate that imperatorin directly interacts with multiple residues situated within the transmembrane substrate-binding pocket of ABCG2. Taken together, these results furnish substantiation that imperatorin holds promise for further evaluation as a potent inhibitor of ABCG2, warranting exploration in combination drug therapy to enhance the effectiveness of therapeutic agents for patients afflicted with tumors that exhibit high levels of ABCG2.
Language	English
Publishing date	2023-11-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16111595
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Article ; Online: Hydroxygenkwanin Improves the Efficacy of Cytotoxic Drugs in ABCG2-Overexpressing Multidrug-Resistant Cancer Cells.

Li, Yan-Qing / Murakami, Megumi / Huang, Yang-Hui / Hung, Tai-Ho / Wang, Shun-Ping / Wu, Yu-Shan / Ambudkar, Suresh V / Wu, Chung-Pu

International journal of molecular sciences

2022 Volume 23, Issue 21

Abstract: Hydroxygenkwanin, a flavonoid isolated from the leaves of ... ...

Abstract	Hydroxygenkwanin, a flavonoid isolated from the leaves of the
MeSH term(s)	Humans ; Drug Resistance, Multiple ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Drug Resistance, Neoplasm ; Neoplasm Proteins/metabolism ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Flavonoids/pharmacology ; ATP-Binding Cassette Transporters/metabolism ; Neoplasms/drug therapy
Chemical Substances	ATP Binding Cassette Transporter, Subfamily G, Member 2 ; hydroxygenkwanin (20243-59-8) ; Neoplasm Proteins ; Antineoplastic Agents ; Flavonoids ; ATP-Binding Cassette Transporters ; ABCG2 protein, human
Language	English
Publishing date	2022-10-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232112763
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Article ; Online: ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

Chung-Pu Wu / Cheng-Yu Hung / Ya-Ju Hsieh / Megumi Murakami / Yang-Hui Huang / Tsung-Yao Su / Tai-Ho Hung / Jau-Song Yu / Yu-Shan Wu / Suresh V. Ambudkar

Cells, Vol 12, Iss 1056, p

2023 Volume 1056

Abstract: Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts ...

Abstract	Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.
Keywords	multidrug resistance ; ABCB1 ; ABCG2 ; PI3K ; HS-173 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The multi-targeted tyrosine kinase inhibitor SKLB610 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs.

Wu, Chung-Pu / Murakami, Megumi / Wu, Yu-Shan / Lin, Chun-Ling / Li, Yan-Qing / Huang, Yang-Hui / Hung, Tai-Ho / Ambudkar, Suresh V

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 149, Page(s) 112922

Abstract: The overexpression of ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein) or ABCG2 (BCRP/MXR/ABCP) in cancer cells is frequently associated with the development of multidrug resistance (MDR) in cancer patients, which remains a major obstacle to ...

Abstract	The overexpression of ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein) or ABCG2 (BCRP/MXR/ABCP) in cancer cells is frequently associated with the development of multidrug resistance (MDR) in cancer patients, which remains a major obstacle to effective cancer treatment. By utilizing energy derived from ATP hydrolysis, both transporters have been shown to reduce the chemosensitivity of cancer cells by actively effluxing cytotoxic anticancer drugs out of cancer cells. Knowing that there are presently no approved drugs or other therapeutics for the treatment of multidrug-resistant cancers, in recent years, studies have investigated the repurposing of tyrosine kinase inhibitors (TKIs) to act as agents against MDR mediated by ABCB1 and/or ABCG2. SKLB610 is a multi-targeted TKI with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor 2 (FGFR2). In this study, we investigate the interaction of SKLB610 with ABCB1 and ABCG2. We discovered that neither ABCB1 nor ABCG2 confers resistance to SKLB610, but SKLB610 selectively sensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer agents in a concentration-dependent manner. Our data indicate that SKLB610 reverses ABCG2-mediated MDR by attenuating the drug-efflux function of ABCG2 without affecting its total cell expression. These findings are further supported by results of SKLB610-stimulated ABCG2 ATPase activity and in silico docking of SKLB610 in the drug-binding pocket of ABCG2. In summary, we reveal the potential of SKLB610 to overcome resistance to cytotoxic anticancer drugs, which offers an additional treatment option for patients with multidrug-resistant cancers and warrants further investigation.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; ATP-Binding Cassette Transporters ; Adenosine Triphosphate/pharmacology ; Antineoplastic Agents/pharmacology ; Benzamides ; Cell Line, Tumor ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Neoplasm Proteins/metabolism ; Neoplasms ; Picolinic Acids ; Protein Kinase Inhibitors/pharmacology ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Antineoplastic Agents ; Benzamides ; N-methyl-4-(4-(3-(trifluoromethyl)benzamido)phenoxy)picolinamide ; Neoplasm Proteins ; Picolinic Acids ; Protein Kinase Inhibitors ; Vascular Endothelial Growth Factor A ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2022-04-05
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.112922
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Article ; Online: The WD repeat-containing protein 5 (WDR5) antagonist WDR5-0103 restores the efficacy of cytotoxic drugs in multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2.

Wu, Chung-Pu / Hsieh, Ya-Ju / Tseng, Han-Yu / Huang, Yang-Hui / Li, Yan-Qing / Hung, Tai-Ho / Wang, Shun-Ping / Wu, Yu-Shan

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 154, Page(s) 113663

Abstract: The development of multidrug resistance (MDR) is one of the major challenges in the treatment of cancer which is caused by the overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and/or ABCG2 (BCRP/MXR/ABCP) in cancer ... ...

Abstract	The development of multidrug resistance (MDR) is one of the major challenges in the treatment of cancer which is caused by the overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and/or ABCG2 (BCRP/MXR/ABCP) in cancer cells. These transporters are capable of reducing the efficacy of cytotoxic drugs by actively effluxing them out of cancer cells. Since there is currently no approved treatment for patients with multidrug-resistant tumors, the drug repurposing approach provides an alternative route to identify agents to reverse MDR mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. WDR5-0103 is a histone H3 lysine 4 (H3K4) methyltransferase inhibitor that disrupts the interaction between the WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia (MLL) protein. In this study, the effect of WDR5-0103 on MDR mediated by ABCB1 and ABCG2 was determined. We found that in a concentration-dependent manner, WDR5-0103 could sensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to conventional cytotoxic drugs. Our results showed that WDR5-0103 reverses MDR and improves drug-induced apoptosis in multidrug-resistant cancer cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, without altering the protein expression of ABCB1 or ABCG2. The potential sites of interactions of WDR5-0103 with the drug-binding pockets of ABCB1 and ABCG2 were predicted by molecular docking. In conclusion, the MDR reversal activity of WDR5-0103 demonstrated here indicates that it could be used in combination therapy to provide benefits to a subset of patients with tumor expressing high levels of ABCB1 or ABCG2.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; ATP-Binding Cassette Transporters ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Molecular Docking Simulation ; Neoplasm Proteins/metabolism ; Neoplasms ; WD40 Repeats
Chemical Substances	ABCB1 protein, human ; ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Antineoplastic Agents ; Intracellular Signaling Peptides and Proteins ; Neoplasm Proteins ; WDR5 protein, human
Language	English
Publishing date	2022-09-05
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.113663
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Article ; Online: Epidermal Growth Factor Receptor Inhibitor Mobocertinib Resensitizes Multidrug-Resistant Cancer Cells by Attenuating the Human ATP-Binding Cassette Subfamily B Member 1 and Subfamily G Member 2.

Li, Yen-Ching / Hsiao, Sung-Han / Murakami, Megumi / Huang, Yang-Hui / Chang, Yu-Tzu / Hung, Tai-Ho / Wu, Yu-Shan / Ambudkar, Suresh V / Wu, Chung-Pu

ACS pharmacology & translational science

2023 Volume 7, Issue 1, Page(s) 161–175

Abstract: ATP-binding cassette (ABC) transporters, notably ABCB1 (P-glycoprotein) and ABCG2, play a crucial role in the development of multidrug resistance (MDR) during the administration of chemotherapy for cancer patients. With a lack of approved treatments for ... ...

Abstract	ATP-binding cassette (ABC) transporters, notably ABCB1 (P-glycoprotein) and ABCG2, play a crucial role in the development of multidrug resistance (MDR) during the administration of chemotherapy for cancer patients. With a lack of approved treatments for addressing multidrug-resistant cancers, MDR remains a substantial challenge to the effective management of cancer. Rather than focusing on developing novel synthetic inhibitors, a promising approach to combat MDR involves repurposing approved therapeutic agents to enhance the sensitivity to cytotoxic antiproliferative drugs of multidrug-resistant cancer cells with high expression of ABCB1 or ABCG2. In this investigation, we observed a substantial reversal of MDR conferred by ABCB1 and ABCG2 in multidrug-resistant cancer cells through the use of mobocertinib, an approved third-generation inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Mobocertinib demonstrated the ability to hinder drug transport function without causing changes in protein expression. The interactions between mobocertinib and ABCB1, as well as ABCG2, were validated through ATPase assays. Furthermore, in silico docking simulations were utilized to substantiate the binding of mobocertinib within the drug-binding pockets of both ABCB1 and ABCG2. We conclude that further testing of mobocertinib in combination therapy is warranted for patients with tumors expressing elevated levels of the ABC drug transporters ABCB1 and ABCG2.
Language	English
Publishing date	2023-12-05
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.3c00217
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Article ; Online: Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells.

Wu, Chung-Pu / Li, Yen-Ching / Murakami, Megumi / Hsiao, Sung-Han / Lee, Yun-Chieh / Huang, Yang-Hui / Chang, Yu-Tzu / Hung, Tai-Ho / Wu, Yu-Shan / Ambudkar, Suresh V

International journal of molecular sciences

2023 Volume 24, Issue 18

Abstract: ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for ... ...

Abstract	ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for multidrug-resistant cancers presents a significant challenge in effectively treating cancer. Researchers propose repurposing existing drugs to sensitize multidrug-resistant cancer cells, which overexpress ABCB1 or ABCG2, to conventional anticancer drugs. The goal of this study is to assess whether furmonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor overcomes drug resistance mediated by ABCB1 and ABCG2 transporters. Furmonertinib stands out due to its ability to inhibit drug transport without affecting protein expression. The discovery of this characteristic was validated through ATPase assays, which revealed interactions between furmonertinib and ABCB1/ABCG2. Additionally, in silico docking of furmonertinib offered insights into potential interaction sites within the drug-binding pockets of ABCB1 and ABCG2, providing a better understanding of the underlying mechanisms responsible for the reversal of MDR by this repurposed drug. Given the encouraging results, we propose that furmonertinib should be explored as a potential candidate for combination therapy in patients with tumors that have high levels of ABCB1 and/or ABCG2. This combination therapy holds the potential to enhance the effectiveness of conventional anticancer drugs and presents a promising strategy for overcoming MDR in cancer treatment.
Language	English
Publishing date	2023-09-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241813972
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