Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

Teodori, Elisabetta; Braconi, Laura; Bua, Silvia; Lapucci, Andrea; Bartolucci, Gianluca; Manetti, Dina; Romanelli, Maria Novella; Dei, Silvia; Supuran, Claudiu T.; Coronnello, Marcella

doi:10.3390/molecules25071748

Cited by 31 publications

(24 citation statements)

References 48 publications

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“…Thus, CA IX was established as an additive prognostic marker [ 45 , 64 ]. In addition, a role of CA IX as a pH sensor was established, and the first therapeutic options by the selective inhibition of carbonic anhydrases, leading to a reversion of the multidrug resistance in tumor cells, were reported [ 65 ].…”

Section: Hif-1α Stabilization Under Normoxia Its Role In Glutaminmentioning

confidence: 99%

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

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et al. 2020

IJMS

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Oral squamous cell carcinoma (OSCC) is the 10th most frequent human malignancy and is thus a global burden. Despite some progress in diagnosis and therapy, patients’ overall survival rate, between 40 and 55%, has stagnated over the last four decades. Since the tumor node metastasis (TNM) system is not precise enough to predict the disease outcome, additive factors for diagnosis, prognosis, prediction and therapy resistance are urgently needed for OSCC. One promising candidate is the hypoxia inducible factor-1 (HIF-1), which functions as an early regulator of tumor aggressiveness and is a key promoter of energy adaptation. Other parameters comprise the composition of the tumor microenvironment, which determines the availability of nutrients and oxygen. In our opinion, these general processes are linked in the pathogenesis of OSCC. Based on this assumption, the review will summarize the major features of the HIF system-induced activities, its target proteins and related pathways of nutrient utilization and metabolism that are essential for the initiation, progression and therapeutic stratification of OSCC.

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Section: Hif-1α Stabilization Under Normoxia Its Role In Glutaminmentioning

confidence: 99%

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

Eckert

Kappler

Große

et al. 2020

IJMS

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“…Abnormal expression of active drug efflux transporters, including P-GP, MRP, LRP, and BCRP, are also involved in the regulation of MDR [ 26 , 27 ]. The current study also investigated the expression of relative drug efflux transporters in HCC cells and tumors.…”

Section: Discussionmentioning

confidence: 99%

Functional Doxorubicin-Loaded Omega-3 Unsaturated Fatty Acids Nanoparticles in Reversing Hepatocellular Carcinoma Multidrug Resistance

2020

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Background This study investigated a nanoparticle drug delivery system to reverse multidrug resistance (MDR) and assessed its anticancer efficacy in hepatocellular carcinoma (HCC). Material/Methods Docosahexaenoic acid (DHA) was used as the functional excipient and doxorubicin (DOX) as the chemotherapeutic drug to synthesize DOX nanoparticles (DOX-nano). The human HCC cell line HepG2 was used for experiments. HepG2/DOX, HepG2+DOX, HepG2+DOX-nano, HepG2/DOX+DOX, and HepG2/DOX+DOX-nano groups cells were treated with DOX or DOX-nano (5 μg/mL). Nude mice bearing a HepG2/DOX xenograft were divided into model, DOX, vector-nano, and DOX-nano groups and injected with saline, DOX reagent, vector-nano, and DOX-nano (2 mg/kg), respectively. Next, cytotoxicity, cellular uptake, cell apoptosis and migration, fluorescence imaging, TUNEL assay, and tumor inhibition effects were assessed in vitro and in vivo. Furthermore, expression of MDR-related proteins was also detected using western blotting. Results Fluorescence imaging showed that the DOX uptake in the DOX-nano-treated group was the strongest in the HCC cells or tumors. Cell apoptosis was significantly increased in DOX-nano-treated HepG2/DOX cells and tumors, and cell migration was significantly inhibited in the DOX-nano-treated HepG2/DOX cells compared with the other groups. The tumor inhibitory rate in DOX-nano-injected tumors was also significantly higher than in other groups. The expression of breast cancer resistance protein, B-cell lymphoma 2, lung resistance protein, multidrug resistance protein, and protein kinase C alpha was significantly decreased in DOX-nano-treated HepG2/DOX cells and xenograft tumors. Significantly better antitumor and MDR-reversing effects were also observed in the HepG2+DOX group compared with the HepG2/DOX group. Conclusions This study revealed the potential efficacy of a DOX-nano drug delivery system for the treatment of HCC, using HepG2/DOX cells and nude mice bearing HepG2/DOX xenografts.

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“…K562 human erythroleukemia parental cell line (ATCC, Rockville, MD, USA) were used [ 21 ]. Cells grew in RPMI 1640 culture medium added with penicillin G 100 U/mL, streptomycin 100 mg/mL, L-glutamine 2 mM and 10% fetal bovine serum (FBS), at 37 °C in a humidified atmosphere at 5% of CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Co-Delivery of Berberine Chloride and Tariquidar in Nanoliposomes Enhanced Intracellular Berberine Chloride in a Doxorubicin-Resistant K562 Cell Line Due to P-gp Overexpression

et al. 2021

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The MDR phenomenon has become a major obstacle in the treatment of cancers, and among the strategies to reverse it, the inhibition of P-gp function and expression is essential to increase for effective anticancer drugs. In the present paper, the co-delivery of berberine chloride and tariquidar loaded nanoliposomes was investigated with the aim of enhancing solubility and improving desired effects for the antineoplastic drug and the P-gp inhibitor. Developed nanoliposomes were loaded with the electron-dense enzyme horseradish peroxidase, and analyzed by TEM to investigate their ability to enter in both K562 and K562/DOXO cell lines. Receptor-mediated endocytosis was evidenced for both cell lines. Nanoliposomes were loaded with tariquidar, berberine chloride, or both, maintaining chemical and physical characteristics—i.e., size, homogeneity, and encapsulation efficiency—and high suitability for parenteral administration. Tariquidar was able to reverse the MDR in the K562/DOXO cell line. Tariquidar- and berberine chloride-loaded nanoliposomes showed a significant increase of berberine chloride accumulation in tumor cells, which could be correlated with resensitization of the resistant cells to the antitumor agent. These results suggest that the co-delivery of the P-gp inhibitor, tariquidar, and the cytotoxicity inducer, berberine chloride, looks like a promising approach to overcome the MDR.

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Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

Cited by 31 publications

References 48 publications

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

Functional Doxorubicin-Loaded Omega-3 Unsaturated Fatty Acids Nanoparticles in Reversing Hepatocellular Carcinoma Multidrug Resistance

Co-Delivery of Berberine Chloride and Tariquidar in Nanoliposomes Enhanced Intracellular Berberine Chloride in a Doxorubicin-Resistant K562 Cell Line Due to P-gp Overexpression

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