Review
Biochemistry & Molecular Biology
Narakorn Khunweeraphong, Karl Kuchler
Summary: Multidrug resistance can be a major issue in cancer treatment and microbial infections, with dysregulated overexpression of ATP-binding cassette transporter members being linked to this phenomenon. High-resolution atomic structures from X-ray crystallography or cryo-EM are helping to improve understanding of the mechanisms and dynamics driving these transporters, offering new perspectives for therapeutic interventions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Plant Sciences
Sara Abdelfatah, Madeleine Boeckers, Maitane Asensio, Onat Kadioglu, Anette Klinger, Edmond Fleischer, Thomas Efferth
Summary: The study identified isopetasin and S-isopetasin as novel P-gp inhibitors, which can overcome multidrug resistance and induce ROS generation and apoptosis in cancer cells.
Article
Biochemistry & Molecular Biology
Keerthana Sasitharan, Hamzah Asad Iqbal, Foteini Bifsa, Aleksandra Olszewska, Kenneth J. Linton
Summary: The study investigates the role of hydrogen bonds and specific glutamines in drug recognition and transport by the ABCB1 efflux transporter. Results show that different glutamine mutations have varying effects on the transport of different drug classes, suggesting a complex mechanism of drug recognition. Surprisingly, some mutations improved drug transport, highlighting the intricate interactions within the drug binding pocket of ABCB1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Diogo Henrique Kita, Gisele Alves de Andrade, Juliana Morais Missina, Kahoana Postal, Viktor Kalbermatter Boell, Francielli Sousa Santana, Ingrid Fatima Zattoni, Isadora da Silva Zanzarini, Vivian Rotuno Moure, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Emanuel Maltempi de Souza, David A. Mitchell, Suresh Ambudkar, Giovana Gioppo Nunes, Glaucio Valdameri
Summary: The study found that polyoxovanadates can serve as inhibitors of ABC drug transporters, selectively inhibiting P-glycoprotein with V-10 and V-18 being the most promising compounds.
Article
Microbiology
Jan Viglas, Petra Olejnikova
Summary: The ABC transporter superfamily plays a crucial role in transporting various molecules across biological membranes, including antifungal compounds in filamentous fungi. Understanding the physiological substrates and roles of individual subfamilies of ABC transporters in fungi is important for clarifying their significance in clinical and agricultural settings.
MICROBIOLOGICAL RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Gangyang Wang, Lingling Cao, Yafei Jiang, Tao Zhang, Hongsheng Wang, Zhuoying Wang, Jing Xu, Min Mao, Yingqi Hua, Zhengdong Cai, Xiaojun Ma, Shuo Hu, Chenghao Zhou
Summary: This study demonstrates that anlotinib can reverse multidrug resistance in osteosarcoma cells by inhibiting the efflux function of P-glycoprotein 1 (PGP1) and increasing the intracellular accumulation of chemotherapeutic agents. Anlotinib also stimulates the ATPase activity of PGP1. In animal studies, anlotinib combined with doxorubicin shows a significant decrease in tumor growth rate and tumor size.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Jingyi Fan, Kenneth Kin Wah To, Zhe-Sheng Chen, Liwu Fu
Summary: Multidrug resistance (MDR) is when cancer cells become resistant to a wide range of unrelated drugs. This hinders cancer treatment and is a major cause of chemotherapy failure. ABC transporters are frequently overexpressed in MDR cancer cells, promoting drug efflux and reducing drug accumulation. Recent evidence suggests that ABC transporters also regulate the tumor immune microenvironment (TIME) by transporting cytokines, influencing anti-tumor immunity and drug sensitivity. Inhibition of ABC transporter expression or function can enhance the efficacy of immune checkpoint inhibitors by promoting an anticancer immune microenvironment. This review provides an update on current research progress in this field.
DRUG RESISTANCE UPDATES
(2023)
Article
Infectious Diseases
Bo Yang, Dongqiang Wang, Mingxiao Liu, Xiaodong Wu, Jigang Yin, Guan Zhu
Summary: The study aimed to generate host cells with resistance to specific anti-cryptosporidial drugs by transiently overexpressing the MDR1 gene. Results showed increased drug tolerance in host cells for certain compounds with varying effects on the anti-parasitic efficacy, highlighting the importance of understanding drug targets in parasite vs. host cells.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2022)
Article
Chemistry, Medicinal
Laura Braconi, Silvia Dei, Marialessandra Contino, Chiara Riganti, Gianluca Bartolucci, Dina Manetti, Maria Novella Romanelli, Maria Grazia Perrone, Nicola Antonio Colabufo, Stefano Guglielmo, Elisabetta Teodori
Summary: New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized and studied as MDR reversers, showing potent inhibitory effects on P-gp transport activity and increasing the antiproliferative effect of doxorubicin in MDR cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Naiara Dutra Barroso Gomes, Emanuel Paula Magalhaes, Lyanna Rodrigues Ribeiro, John Washington Cavalcante, Marcelo Morais Gomes Maia, Felipe Ramon Cunha da Silva, Arif Ali, Marcia Machado Marinho, Emmanuel Silva Marinho, Helcio Silva dos Santos, Alice Maria Costa Martins, Ramon Roseo Paula Pessoa Bezerra de Menezes
Summary: This study evaluated the activity of synthetic p-aminochalcones against T. cruzi and found that they have a trypanocidal effect by causing membrane damage and oxidative stress. Their mechanism of action may be related to inhibition of cruzain and TR.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Physical
Damian Krzyzanowski, Marcin Kruszewski, Agnieszka Grzelak
Summary: Silver nanoparticles (AgNPs) have unique properties that have attracted significant attention, showing antibacterial, antifungal, and anticancer properties. However, they can also exhibit cytotoxic effects and modulate the activity and expression of ABC transporters.
Article
Biochemistry & Molecular Biology
Keita Matsuoka, Toru Nakatsu, Hiroaki Kato
Summary: This study reported the crystal structure of the outward-facing state of the CmABCB1 G132V mutant, showing that the conformational change caused by the valine substitution led to an increase in ATPase activity, although the specific mechanism behind this remains unclear.
Article
Parasitology
Davi Alvarenga Lima, Leilane Oliveira Goncalves, Joao Luis Reis-Cunha, Paul Anderson Souza Guimaraes, Jeronimo Conceicao Ruiz, Daniel Barbosa Liarte, Silvane Maria Fonseca Murta
Summary: This study performed comparative transcriptomic analysis of wildtype and benznidazole-resistant T. cruzi populations, revealing metabolic pathways related to clinical drug resistance and identifying promising molecular targets for the development of new drugs for Chagas disease.
PARASITES & VECTORS
(2023)
Article
Pharmacology & Pharmacy
John Golin, Lutz Schmitt
Summary: Pdr5 is a founding member of a large subfamily of fungal ABC transporters and its remarkable asymmetry is manifested in its ATP-binding sites, drug binding sites, signal transformation interface, and molecular exit gate. The noncanonical ATP site and gating residues in Pdr5 have different essential functions compared to their canonical counterparts.
DRUG RESISTANCE UPDATES
(2023)
Article
Biochemistry & Molecular Biology
Liadys Mora Lagares, Yunierkis Perez-Castillo, Nikola Minovski, Marjana Novic
Summary: P-gp is an important protein involved in drug efflux and multidrug resistance. Molecular dynamics simulations can provide valuable insights into the binding behavior and conformational changes of P-gp in the presence of different compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Thais Oliveira, Douglas Lemos, Louise Jean, Jessica M. Kawashima, Vitoria R. de Azevedo, Eduardo J. Salustiano, Vivian M. Rumjanek, Robson Q. Monteiro
Summary: This study found that disrupting the hexokinase II in multidrug resistant cells of chronic myeloid leukemia can impair bioenergetic parameters, increase drug accumulation, and induce cell death. This could be a promising strategy for the management of chemotherapy-refractory patients.
FRONTIERS IN ONCOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Israel Diniz-Lima, Leonardo Marques da Fonseca, Elias Barbosa da Silva-Junior, Joyce Cristina Guimaraes-de-Oliveira, Leonardo Freire-de-Lima, Danielle Oliveira Nascimento, Alexandre Morrot, Jose Osvaldo Previato, Lucia Mendonca-Previato, Debora Decote-Ricardo, Celio Geraldo Freire-de-Lima
Summary: Cryptococcosis is caused by pathogenic fungi, including Cryptococcus neoformans and Cryptococcus gattii. The latter causes severe undiscriminating infections in immunocompetent individuals and is becoming more prevalent due to climatic factors. The immunopathology of cryptococcosis caused by C. gattii is still poorly understood, but research has helped to uncover its different variants.
APPLIED SCIENCES-BASEL
(2022)
Review
Microbiology
Kelli Monteiro da Costa, Raphael do Carmo Valente, Leonardo Marques da Fonseca, Leonardo Freire-de-Lima, Jose Osvaldo Previato, Lucia Mendonca-Previato
Summary: Human trypanosomiasis has a significant impact on the global population, affecting around 8 million people, particularly in endemic areas. Resistance to chemotherapy has been observed in protozoan parasites, including the T. cruzi and T. brucei species. ABC transporters, which reduce drug accumulation and mitigate toxic effects, have been identified as important factors in multidrug resistance. This review provides an overview of the history and function of ABC transporters in Trypanosoma species, highlighting their significance in parasite physiology and chemotherapy resistance.
Article
Microbiology
Elias Barbosa Da Silva-Junior, Israel Diniz-Lima, Amanda Couto Silva, Joyce Cristina Guimaraes-de-Oliveira, Alexandre Morrot, Leonardo Freire-de-Lima, Leonardo Marques da Fonseca, Lycia De Brito-Gitirana, Debora Decote-Ricardo, Herbert Leonel de Matos Guedes, Celio Geraldo Freire-de-Lima
Summary: This study demonstrates that TLR9-deficient mice are more susceptible to C. gattii infection and exhibit more severe pathological changes, confirming the importance of TLR9 in countering C. gattii infection.
Article
Infectious Diseases
Paulo Pitasse-Santos, Eduardo Salustiano, Raynna Bittencourt Pena, Otavio Augusto Chaves, Leonardo Marques da Fonseca, Kelli Monteiro da Costa, Carlos Antonio do Nascimento Santos, Jhenifer Santos Dos Reis, Marcos Andre Rodrigues da Costa Santos, Jose Osvaldo Previato, Lucia Mendonca Previato, Leonardo Freire-de-Lima, Nelilma Correia Romeiro, Lucia Helena Pinto-da-Silva, Celio G. Freire-de-Lima, Debora Decote-Ricardo, Marco Edilson Freire-de-Lima
Summary: Cancer and parasitic diseases share similarities, and a new strategy of developing antiproliferative agents is proposed. A series of 1,2,4-oxadiazole compounds were designed and a fast and efficient synthesis strategy was developed. Compound 23 exhibited antiproliferative activity against cancer and parasites, and interacted with tubulin. In silico predictions showed that these compounds have high druggability potential, and compound 23 can bind with human serum albumin.
TROPICAL MEDICINE AND INFECTIOUS DISEASE
(2022)
Review
Microbiology
Israel Diniz-Lima, Leonardo Marques da Fonseca, Jhenifer Santos Dos Reis, Debora Decote-Ricardo, Alexandre Morrot, Jose Osvaldo Previato, Lucia Mendonca Previato, Celio Geraldo Freire-de-Lima, Leonardo Freire-de-Lima
Summary: Invasive fungal infections (IFI) are a major cause of death, particularly in immunocompromised patients undergoing chemotherapy for cancer. The interferences that IFI may have on cancer progression and the induction of new cancer cells have been increasingly recognized. Fungal virulence factors, particularly the polysaccharide capsule in cryptococcosis, play a significant role in modulating the immune system and potentially affecting cancer development and progression. This article discusses the relationship between cryptococcosis and cancer progression, as well as the implications of fungal glycan structures in cancer.
BRAZILIAN JOURNAL OF MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kelli Monteiro da Costa, Leonardo Freire-de-Lima, Leonardo Marques da Fonseca, Jose Osvaldo Previato, Lucia Mendonca-Previato, Raphael do Carmo Valente
Summary: Multidrug resistance (MDR) and induction of metastasis are challenges in cancer chemotherapy. The ABC transporters play a role in MDR, while metastasis is associated with epithelial-mesenchymal transition (EMT). The study showed increased expression of ABCB1 and ABCC1 during EMT, with ABCC1 inhibitors partially inhibiting EMT-marker snail.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Editorial Material
Microbiology
Debora Decote-Ricardo, Danielle de Oliveira Nascimento, Leonardo Freire-de-Lima, Alexandre Morrot, Celio Geraldo Freire-de-Lima
Article
Biology
Jorgete Logullo, Israel Diniz-Lima, Juliana Dutra B. Rocha, Suzana Corte-Real, Elias Barbosa da Silva-Junior, Joyce Cristina Guimaraes-de-Oliveira, Alexandre Morrot, Leonardo Marques da Fonseca, Leonardo Freire-de-Lima, Debora Decote-Ricardo, Celio Geraldo Freire-de-Lima
Summary: The interaction between cells and the extracellular matrix affects the plasticity and migratory capacity of cells. Macrophages play a crucial role in immunity by migrating and adhering to tissues through their adhesion receptors. In vitro models using synthetic matrices have been used to study the dynamics of cell-matrix interactions, particularly in infectious diseases such as Chagas disease caused by the parasite Trypanosoma cruzi. This study demonstrates that the macrophage-matrix interaction promotes T. cruzi replication, alters macrophage morphology, and induces migratory macrophages.
Article
Biochemistry & Molecular Biology
Jhenifer Santos dos Reis, Marcos Andre Rodrigues da Costa Santos, Kelli Monteiro da Costa, Celio Geraldo Freire-de-Lima, Alexandre Morrot, Jose Osvaldo Previato, Lucia Mendonca Previato, Leonardo Marques da Fonseca, Leonardo Freire-de-Lima
Summary: Changes in protein glycosylation are a characteristic feature of transformed cells and play a role in cancer progression, including the development of multidrug resistance (MDR). UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-6 (pp-GalNAc-T6) is a glycosyltransferase involved in various events associated with cancer progression. This study demonstrates the role of pp-GalNAc-T6 in the acquisition of MDR phenotype in breast cancer cells, showing that its expression is upregulated along with the O-glycosylation of oncofetal fibronectin (onf-FN) during MDR development. Silencing pp-GalNAc-T6 not only decreases onf-FN expression but also makes MDR cells more sensitive to anticancer drugs, partially reversing the MDR phenotype.
Review
Infectious Diseases
Kamila Guimaraes-Pinto, Jesuino R. M. Ferreira, Andre L. A. da Costa, Alexandre Morrot, Leonardo Freire-de-Lima, Debora Decote-Ricardo, Celio Geraldo Freire-de-Lima, Alessandra A. Filardy
Summary: Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi infection. Excessive immune system stimulation driven by parasite persistence may lead to the deterioration of immune functions and the progression of Chagas disease. Understanding the chronic inflammatory status induced by T. cruzi and its effects on host defense capacity could provide insights for developing therapeutic approaches for the prevention and treatment of Chagas disease.
TROPICAL MEDICINE AND INFECTIOUS DISEASE
(2022)
Review
Infectious Diseases
Ana Caroline Costa-da-Silva, Danielle de Oliveira Nascimento, Jesuino R. M. Ferreira, Kamila Guimaraes-Pinto, Leonardo Freire-de-Lima, Alexandre Morrot, Debora Decote-Ricardo, Alessandra Almeida Filardy, Celio Geraldo Freire-de-Lima
Summary: Leishmaniasis is a widespread and neglected parasitic disease caused by various species of Leishmania, with severity depending on multiple factors. This article discusses the role of the immune system, its molecules, and responses in the development of Leishmaniasis, focusing on the interactions between innate immune cells and Leishmania major.
TROPICAL MEDICINE AND INFECTIOUS DISEASE
(2022)