Latest Publications

@article{besse_hiv-protease_2024,

title = {HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer.},

author = {Andrej Besse and Lenka Sedlarikova and Lorina Buechler and Marianne Kraus and Chieh-Hsiang Yang and Nicol Strakova and Karel Soucek and Jiri Navratil and Marek Svoboda and Alana L. Welm and Markus Joerger and Christoph Driessen and Lenka Besse},

doi = {10.1038/s41416-024-02774-9},

issn = {1532-1827 0007-0920},

year  = {2024},

date = {2024-09-01},

journal = {British journal of cancer},

volume = {131},

number = {5},

pages = {918–930},

abstract = {BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.},

note = {Place: England},

keywords = {*ATP Binding Cassette Transporter, *Bortezomib/pharmacology, *Drug Synergism, *HIV Protease Inhibitors/pharmacology, *Lopinavir/pharmacology, *Nelfinavir/pharmacology, *Oligopeptides/pharmacology, *Triple Negative Breast Neoplasms/drug therapy/pathology, *Unfolded Protein Response/drug effects, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Apoptosis/drug effects, ATP Binding Cassette Transporter, Cell Line, Endoplasmic Reticulum Stress/drug effects, Female, Humans, Member 2/metabolism/antagonists & inhibitors, Neoplasm Proteins/antagonists & inhibitors/metabolism, Proteasome Inhibitors/pharmacology, Subfamily B/metabolism, Subfamily G, Tumor, X-Box Binding Protein 1/metabolism/genetics},

pubstate = {published},

tppubtype = {article}

}

@article{vargova_hypericin_2018,

title = {Hypericin affects cancer side populations via competitive inhibition of BCRP.},

author = {Jana Vargová and Jaromír Mikeš and Rastislav Jendželovský and Lucia Mikešová and Barbora Kuchárová and Ľubomír Čulka and Radek Fedr and Ján Remšík and Karel Souček and Alois Kozubík and Peter Fedoročko},

doi = {10.1016/j.biopha.2018.01.074},

issn = {1950-6007 0753-3322},

year  = {2018},

date = {2018-03-01},

journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},

volume = {99},

pages = {511–522},

abstract = {OBJECTIVE: Cancer stem-like cells (CSLCs) are considered a root of tumorigenicity and resistance. However, their identification remains challenging. The use of the side population (SP) assay as a credible marker of CSLCs remains controversial. The SP assay relies on the elevated activity of ABC transporters that, in turn, can be modulated by hypericin (HYP), a photosensitizer and bioactive compound of St. John's Wort (Hypericum perforatum), a popular over-the-counter antidepressant. Here we aimed to comprehensively characterize the SP phenotype of cancer cells and to determine the impact of HYP on these cells. METHODS: Flow cytometry and sorting-based assays were employed, including CD24-, CD44-, CD133-, and ALDH-positivity, clonogenicity, 3D-forming ability, ABC transporter expression and activity, and intracellular accumulation of HYP/Hoechst 33342. The tumorigenic ability of SP, nonSP, and HYP-treated cells was verified by xenotransplantation into immunodeficient mice. RESULTS: The SP phenotype was associated with elevated expression of several investigated transporters and more intensive growth in non-adherent conditions but not with higher clonogenicity, tumorigenicity or ALDH-positivity. Despite stimulated BCRP level and MRP1 activity, HYP reversibly decreased the SP proportion, presumably via competitive inhibition of BCRP. HYP-selected SP cells acquired additional traits of resistance and extensively eliminated HYP. CONCLUSIONS: Our results suggest that SP is not an unequivocal CSLC-marker. However, SP could play an important role in modulating HYP-treatment and serve as a negative predictive tool for HYP-based therapies. Moreover, the use of supplements containing HYP by cancer patients should be carefully considered, due to its proposed effect on drug efflux and complex impact on tumor cells, which have not yet been sufficiently characterized.},

note = {Place: France},

keywords = {ABC transporters, Aldehyde Dehydrogenase/metabolism, Animals, Anthracenes, ATP Binding Cassette Transporter, Biomarkers, Cancer stem-like cells, Carcinogenesis/drug effects/metabolism/pathology, Cell Line, Cellular/drug effects/metabolism/pathology, Clone Cells, Drug resistance, Humans, Hypericin, Member 1/metabolism, Member 2/*metabolism, Mice, Neoplasm Proteins/*metabolism, Neoplasms/*metabolism/*pathology, Neoplastic Stem Cells/drug effects/metabolism/pathology, Perylene/*analogs & derivatives/pharmacology, Phenotype, SCID, Side population, Side-Population Cells/drug effects/*pathology, Spheroids, St. John’s wort, Subfamily B, Subfamily G, Substrate Specificity/drug effects, Survival Analysis, Tumor, Tumor/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{jendzelovsky_drug_2009,

title = {Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells.},

author = {Rastislav Jendzelovský and Jaromír Mikes and Ján Koval' and Karel Soucek and Jirina Procházková and Martin Kello and Veronika Sacková and Jirina Hofmanová and Alois Kozubík and Peter Fedorocko},

doi = {10.1039/b9pp00086k},

issn = {1474-9092 1474-905X},

year  = {2009},

date = {2009-12-01},

journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},

volume = {8},

number = {12},

pages = {1716–1723},

abstract = {Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.},

note = {Place: England},

keywords = {Adenocarcinoma/*drug therapy/secondary, Anthracenes, ATP Binding Cassette Transporter, ATP-Binding Cassette Transporters/*metabolism, Caspase 3/metabolism, Caspase 9/metabolism, Colonic Neoplasms/*drug therapy, Enzyme Inhibitors/pharmacology, HT29 Cells, Humans, Light, Member 1/metabolism, Member 2, Membrane Potential, Mitochondrial/drug effects, Mixed Function Oxygenases/metabolism, Multidrug Resistance-Associated Proteins/*metabolism, Neoplasm Proteins/*metabolism, Perylene/*analogs & derivatives/pharmacology, Photochemotherapy, Photosensitizing Agents/*pharmacology, Proadifen/pharmacology, Reactive Oxygen Species/metabolism, Subfamily B, Subfamily G},

pubstate = {published},

tppubtype = {article}

}