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Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 19045

Special Issue Editor

Prof. Dr. Maria José Umbelino Ferreira

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Guest Editor
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
Interests: natural products; medicinal plants; plant-derived compounds; isolation and molecular derivatization; anticancer agents; multidrug resistance (MDR); ABC-transporter inhibitors; P-glycoprotein (P-gp); antibacterial
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As is widely known, cancer is a major burden of disease globally. Multidrug resistance (MDR), a complex and multifactorial phenomenon, is one of the main impairments in successful cancer chemotherapy. Similarly, the rise and spread of antimicrobial resistance, which may occur in bacteria, viruses, fungi, and parasites, is one the most important public health threats worldwide, making common infectious diseases difficult to treat or not treatable, and a leading cause of death. Although resistance in cancer and microorganisms can arise owing to multiple factors, drug efflux, by transporter proteins, is one of the major reasons of the MDR phenotype.

Natural products, characterized by huge chemical diversity and privileged scaffolds, coupled with a broad range of biological activities, have long been playing a decisive role in drug discovery and development, namely to treat cancer and infectious diseases. Today, many natural product-derived compounds have shown promising potential as MDR reversers, in both resistant cancer cells and microorganisms, thus deserving interest from natural product chemists and medicinal chemists.

This Special Issue on “Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms” invites researchers to contribute with original research or updated review articles focused on relevant natural compounds, obtained by isolation from natural sources, or semisynthetic derivatives, as MDR reversers in cancer and infectious diseases.

Prof. Dr. Maria José Umbelino Ferreira
Guest Editor

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Keywords

  • natural products
  • plant-derived compounds
  • semisynthetic derivatives
  • anticancer agents
  • resistant cancer cells
  • antimicrobial resistance
  • multidrug resistance (MDR)

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Published Papers (7 papers)

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18 pages, 4050 KiB  
Article
APTC-C-SA01: A Novel Bacteriophage Cocktail Targeting Staphylococcus aureus and MRSA Biofilms
by Sha Liu, Karen Hon, George Spyro Bouras, Alkis James Psaltis, Keith Shearwin, Peter-John Wormald and Sarah Vreugde
Int. J. Mol. Sci. 2022, 23(11), 6116; https://doi.org/10.3390/ijms23116116 - 30 May 2022
Cited by 13 | Viewed by 4025
Abstract
The high infection and mortality rate of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the urgent development of new treatment strategies. Bacteriophages (phages) have several advantages compared to antibiotics for the treatment of multi-drug-resistant bacterial infections, and thus provide a promising alternative to antibiotics. Here, [...] Read more.
The high infection and mortality rate of methicillin-resistant Staphylococcus aureus (MRSA) necessitates the urgent development of new treatment strategies. Bacteriophages (phages) have several advantages compared to antibiotics for the treatment of multi-drug-resistant bacterial infections, and thus provide a promising alternative to antibiotics. Here, S. aureus phages were isolated from patients and environmental sources. Phages were characterized for stability, morphology and genomic sequence and their bactericidal activity against the biofilm form of methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA was investigated. Four S. aureus phages were isolated and tested against 51 MSSA and MRSA clinical isolates and reference strains. The phages had a broad host range of 82–94% individually and of >98% when combined and could significantly reduce the viability of S. aureus biofilms. The phages had a latent period of ≤20 min and burst size of >11 plaque forming units (PFU)/infected cell. Transmission electron microscopy (TEM) identified phages belonging to the family of Myoviridae. Genomic sequencing indicated the lytic nature of all four phages, with no identified resistance or virulence genes. The 4 phages showed a high complementarity with 49/51 strains (96%) sensitive to at least 2/4 phages tested. Furthermore, the frequency of bacteriophage insensitive mutant (BIM) generation was lower when the phages were combined into the phage cocktail APTC-C-SA01 than for bacteria exposed to each of the phages alone. In conclusion, APTC-C-SA01, containing four lytic S. aureus phages has the potential for further development as a treatment against MSSA and MRSA infections. Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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17 pages, 8438 KiB  
Article
Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation
by Ming-Fang Wu, Yen-Hsiang Huang, Ling-Yen Chiu, Shur-Hueih Cherng, Gwo-Tarng Sheu and Tsung-Ying Yang
Int. J. Mol. Sci. 2022, 23(15), 8248; https://doi.org/10.3390/ijms23158248 - 26 Jul 2022
Cited by 36 | Viewed by 3499
Abstract
This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen [...] Read more.
This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells. Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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19 pages, 3713 KiB  
Article
Optimized Antimicrobial Peptide Jelleine-I Derivative Br-J-I Inhibits Fusobacterium Nucleatum to Suppress Colorectal Cancer Progression
by Fengjing Jia, Qun Yu, Ruolei Wang, Ling Zhao, Fuwen Yuan, Haidong Guo, Yunhui Shen and Feng He
Int. J. Mol. Sci. 2023, 24(2), 1469; https://doi.org/10.3390/ijms24021469 - 11 Jan 2023
Cited by 16 | Viewed by 2841
Abstract
Colorectal cancer (CRC) is a major health burden worldwide due to its high morbidity, mortality, and complex etiology. Fusobacterium nucleatum (Fn), a Gram-negative anaerobe found in 30% of CRC patients, promotes CRC carcinogenesis, metastasis, and chemoresistance. Effective antimicrobial treatment is an [...] Read more.
Colorectal cancer (CRC) is a major health burden worldwide due to its high morbidity, mortality, and complex etiology. Fusobacterium nucleatum (Fn), a Gram-negative anaerobe found in 30% of CRC patients, promotes CRC carcinogenesis, metastasis, and chemoresistance. Effective antimicrobial treatment is an unmet need for the rising CRC burden. Antimicrobial peptides (AMPs) represent a new class of antimicrobial drugs. In our previous study, we did the structure-activity study of Jelleine-I (J-I) and identified several halogenated J-I derivatives Cl-J-I, Br-J-I, and I-J-I. To determine whether those J-I derivatives can be a new therapy for bacterial-associated CRC, here we tested the antibacterial activities of these AMPs against Fn and their effects on CRC development. We found that Br-J-I showed the highest anti-Fn activity and Br-J-I may target membrane-associated FadA for Fn membrane disruption. More importantly, Fn promoted the growth of CRC cells-derived xenograft tumors. Br-J-I suppressed Fn load, colon inflammation, and Fn-induced CRC growth. Of note, Br-J-I induced better anti-CRC effects than common antibiotic metronidazole and Br-J-I sensitized the cancer-killing effect of chemotherapy drug 5-fluorouracil. These results suggest that Br-J-I could be considered as an adjunctive agent for CRC treatment and AMPs-based combination treatment is a new strategy for CRC in the future. Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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22 pages, 16182 KiB  
Article
Lycorine Carbamate Derivatives for Reversing P-glycoprotein-Mediated Multidrug Resistance in Human Colon Adenocarcinoma Cells
by Shirley A. R. Sancha, Nikoletta Szemerédi, Gabriella Spengler and Maria-José U. Ferreira
Int. J. Mol. Sci. 2023, 24(3), 2061; https://doi.org/10.3390/ijms24032061 - 20 Jan 2023
Cited by 11 | Viewed by 2011
Abstract
Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2– [...] Read more.
Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2–32) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds 1–32 were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound 5, bearing a benzyl substituent, and compounds 9 and 25, with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds (2, 5, 9, 19, 25, and 26) were shown to behave as inhibitors. Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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23 pages, 10483 KiB  
Article
In Vivo Reversal of P-Glycoprotein-Mediated Drug Resistance in a Breast Cancer Xenograft and in Leukemia Models Using a Novel, Potent, and Nontoxic Epicatechin EC31
by Wenqin Sun, Iris L. K. Wong, Helen Ka-Wai Law, Xiaochun Su, Terry C. F. Chan, Gege Sun, Xinqing Yang, Xingkai Wang, Tak Hang Chan, Shengbiao Wan and Larry M. C. Chow
Int. J. Mol. Sci. 2023, 24(5), 4377; https://doi.org/10.3390/ijms24054377 - 22 Feb 2023
Cited by 5 | Viewed by 2571
Abstract
The modulation of P-glycoprotein (P-gp, ABCB1) can reverse multidrug resistance (MDR) and potentiate the efficacy of anticancer drugs. Tea polyphenols, such as epigallocatechin gallate (EGCG), have low P-gp-modulating activity, with an EC50 over 10 μM. In this study, we optimized a series [...] Read more.
The modulation of P-glycoprotein (P-gp, ABCB1) can reverse multidrug resistance (MDR) and potentiate the efficacy of anticancer drugs. Tea polyphenols, such as epigallocatechin gallate (EGCG), have low P-gp-modulating activity, with an EC50 over 10 μM. In this study, we optimized a series of tea polyphenol derivatives and demonstrated that epicatechin EC31 was a potent and nontoxic P-gp inhibitor. Its EC50 for reversing paclitaxel, doxorubicin, and vincristine resistance in three P-gp-overexpressing cell lines ranged from 37 to 249 nM. Mechanistic studies revealed that EC31 restored intracellular drug accumulation by inhibiting P-gp-mediated drug efflux. It did not downregulate the plasma membrane P-gp level nor inhibit P-gp ATPase. It was not a transport substrate of P-gp. A pharmacokinetic study revealed that the intraperitoneal administration of 30 mg/kg of EC31 could achieve a plasma concentration above its in vitro EC50 (94 nM) for more than 18 h. It did not affect the pharmacokinetic profile of coadministered paclitaxel. In the xenograft model of the P-gp-overexpressing LCC6MDR cell line, EC31 reversed P-gp-mediated paclitaxel resistance and inhibited tumor growth by 27.4 to 36.1% (p < 0.001). Moreover, it also increased the intratumor paclitaxel level in the LCC6MDR xenograft by 6 fold (p < 0.001). In both murine leukemia P388ADR and human leukemia K562/P-gp mice models, the cotreatment of EC31 and doxorubicin significantly prolonged the survival of the mice (p < 0.001 and p < 0.01) as compared to the doxorubicin alone group, respectively. Our results suggested that EC31 was a promising candidate for further investigation on combination therapy for treating P-gp-overexpressing cancers. Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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16 pages, 2048 KiB  
Article
In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals
by Julia Schäfer, Vincent Julius Klösgen, Ejlal A. Omer, Onat Kadioglu, Armelle T. Mbaveng, Victor Kuete, Andreas Hildebrandt and Thomas Efferth
Int. J. Mol. Sci. 2023, 24(12), 10240; https://doi.org/10.3390/ijms241210240 - 16 Jun 2023
Cited by 4 | Viewed by 2027
Abstract
Cancer therapy with clinically established anticancer drugs is frequently hampered by the development of drug resistance of tumors and severe side effects in normal organs and tissues. The demand for powerful, but less toxic, drugs is high. Phytochemicals represent an important reservoir for [...] Read more.
Cancer therapy with clinically established anticancer drugs is frequently hampered by the development of drug resistance of tumors and severe side effects in normal organs and tissues. The demand for powerful, but less toxic, drugs is high. Phytochemicals represent an important reservoir for drug development and frequently exert less toxicity than synthetic drugs. Bioinformatics can accelerate and simplify the highly complex, time-consuming, and expensive drug development process. Here, we analyzed 375 phytochemicals using virtual screenings, molecular docking, and in silico toxicity predictions. Based on these in silico studies, six candidate compounds were further investigated in vitro. Resazurin assays were performed to determine the growth-inhibitory effects towards wild-type CCRF-CEM leukemia cells and their multidrug-resistant, P-glycoprotein (P-gp)-overexpressing subline, CEM/ADR5000. Flow cytometry was used to measure the potential to measure P-gp-mediated doxorubicin transport. Bidwillon A, neobavaisoflavone, coptisine, and z-guggulsterone all showed growth-inhibitory effects and moderate P-gp inhibition, whereas miltirone and chamazulene strongly inhibited tumor cell growth and strongly increased intracellular doxorubicin uptake. Bidwillon A and miltirone were selected for molecular docking to wildtype and mutated P-gp forms in closed and open conformations. The P-gp homology models harbored clinically relevant mutations, i.e., six single missense mutations (F336Y, A718C, Q725A, F728A, M949C, Y953C), three double mutations (Y310A-F728A; F343C-V982C; Y953A-F978A), or one quadruple mutation (Y307C-F728A-Y953A-F978A). The mutants did not show major differences in binding energies compared to wildtypes. Closed P-gp forms generally showed higher binding affinities than open ones. Closed conformations might stabilize the binding, thereby leading to higher binding affinities, while open conformations may favor the release of compounds into the extracellular space. In conclusion, this study described the capability of selected phytochemicals to overcome multidrug resistance. Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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4 pages, 216 KiB  
Editorial
Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms
by Maria-José U. Ferreira
Int. J. Mol. Sci. 2023, 24(18), 14321; https://doi.org/10.3390/ijms241814321 - 20 Sep 2023
Cited by 2 | Viewed by 1085
Abstract
Natural products, characterized by huge scaffold diversity, complexity, and bioactivity, have long played a crucial role in drug discovery and development, particularly as anticancer and anti-infective agents [...] Full article
(This article belongs to the Special Issue Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms)
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