10 research outputs found
Potenciális bioaktivitással rendelkező cinkona alapú organokatalizátorok vizsgálata: Study of cinchona-based organocatalysts with potential bioactivity
One of the major representatives of organocatalysts is the group of cinchona alkaloids, which, in addition to their outstanding role in organic synthesis, also have diverse biological effects. An excellent example is quinine, a long-known and generally used antimalarial agent possessing anticancer activity as well, thus the study of bioactivity and anticancer toxicity of other organocatalysts may be a question of interest.
Multidrug resistance (MDR) is the main reason for the failure of chemotherapy, owing to the process in which malignant tumor cells develop resistance towards the cytotoxic agents used during the treatment. One of the most significant mechanisms of MDR is the elevated expression of P-glycoprotein (Pgp, ABCB1, MDR1), a protein belonging to the family of ABC (ATP-binding cassette) transporters, which recognizes many chemotherapeutic compounds as its substrate. We aimed to synthesize amine, thiourea, and squaramide derivatives from quinine, which, based on previous results of our research group, are presumably able to eliminate multidrug-resistant cells overexpressing Pgp. The synthesized compounds were tested and evaluated on parental and MDR cancer cell lines. Chemotypes have been successfully characterized in terms of cytotoxicity and resistance.
Kivonat
Az organokatalizátorok egy jelentős képviselői a cinkona alkaloidok, amelyek kémiai szerepük mellett változatos biológiai hatással is rendelkeznek. Ennek kiváló példája a kinin, amely egy régóta ismert és alkalmazott maláriaellenes szer, rákellenes hatással is rendelkezik, így érdekes kérdésként vetődhet fel további organokatalizátorok bioaktivitásának, rákellenes toxicitásának vizsgálata.
A rosszindulatú tumorok kezelése során alkalmazott kemoterápia gyakran azért vall kudarcot, mert a tumorsejtek rezisztenssé válnak az alkalmazott citotoxikus szerekre, kialakul a multidrog rezisztencia (MDR). Az MDR egyik legjelentősebb mechanizmusa az ABC (ATP-binding cassette) transzporterek családjába tartozó P-glikoprotein (Pgp, ABCB1, MDR1) fehérje fokozott expressziója, amely számos kemoterápiás vegyületet szubsztrátjaként ismer fel. Célunk a kininből kiindulva olyan amin, tiokarbamid és négyzetamid származékok szintézise volt, amelyek a kutatócsoportunk korábbi eredményei alapján feltételezhetően képesek eliminálni a Pgp-t túlexpresszáló multidrog rezisztens sejteket. A szintetizált vegyületek tesztelését parentális és MDR rákos sejtvonalakon végeztük. Citotoxicitás és rezisztencia terén is sikeresen jellemeztük a kemotípusokat
Establishment and Characterization of a Brca1-/-, p53-/- Mouse Mammary Tumor Cell Line.
Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. By the age of 80, the estimated risk for breast cancer for women with germline BRCA1 or BRCA2 mutations is around 80%. Genetically engineered BRCA1-deficient mouse models offer a unique opportunity to study the pathogenesis and therapy of triple negative breast cancer. Here we present a newly established Brca1-/-, p53-/- mouse mammary tumor cell line, designated as CST. CST shows prominent features of BRCA1-mutated triple-negative breast cancers including increased motility, high proliferation rate, genome instability and sensitivity to platinum chemotherapy and PARP inhibitors (olaparib, veliparib, rucaparib and talazoparib). Genomic instability of CST cells was confirmed by whole genome sequencing, which also revealed the presence of COSMIC (Catalogue of Somatic Mutations in Cancer) mutation signatures 3 and 8 associated with homologous recombination (HR) deficiency. In vitro sensitivity of CST cells was tested against 11 chemotherapy agents. Tumors derived from orthotopically injected CST-mCherry cells in FVB-GFP mice showed sensitivity to cisplatin, providing a new model to study the cooperation of BRCA1-KO, mCherry-positive tumor cells and the GFP-expressing stromal compartment in therapy resistance and metastasis formation. In summary, we have established CST cells as a new model recapitulating major characteristics of BRCA1-negative breast cancers
Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer.
Success of cancer treatment is often hampered by the emergence of multidrug resistance (MDR) mediated by P-glycoprotein (ABCB1/Pgp). Doxorubicin (DOX) is recognized by Pgp and therefore it can induce therapy resistance in breast cancer patients. In this study our aim was to evaluate the susceptibility of the pegylated liposomal formulation of doxorubicin (PLD/Doxil(R)/Caelyx(R)) to MDR. We show that cells selected to be resistant to DOX are cross-resistant to PLD and PLD is also ineffective in an allograft model of doxorubicin-resistant mouse B-cell leukemia. In contrast, PLD was far more efficient than DOX as reflected by a significant increase of both relapse-free and overall survival of Brca1-/-;p53-/- mammary tumor bearing mice. Increased survival could be explained by the delayed onset of drug resistance. Consistent with the higher Pgp levels needed to confer resistance, PLD administration was able to overcome doxorubicin insensitivity of the mouse mammary tumors. Our results indicate that the favorable pharmacokinetics achieved with PLD can effectively overcome Pgp-mediated resistance, suggesting that PLD therapy could be a promising strategy for the treatment of therapy-resistant breast cancer patients
Cytotoxicity of cinchona alkaloid organocatalysts against MES-SA and MES-SA/Dx5 multidrug-resistant uterine sarcoma cell lines
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Establishment and Characterization of a Brca1-/-, p53-/- Mouse Mammary Tumor Cell Line.
Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. By the age of 80, the estimated risk for breast cancer for women with germline BRCA1 or BRCA2 mutations is around 80%. Genetically engineered BRCA1-deficient mouse models offer a unique opportunity to study the pathogenesis and therapy of triple negative breast cancer. Here we present a newly established Brca1-/-, p53-/- mouse mammary tumor cell line, designated as CST. CST shows prominent features of BRCA1-mutated triple-negative breast cancers including increased motility, high proliferation rate, genome instability and sensitivity to platinum chemotherapy and PARP inhibitors (olaparib, veliparib, rucaparib and talazoparib). Genomic instability of CST cells was confirmed by whole genome sequencing, which also revealed the presence of COSMIC (Catalogue of Somatic Mutations in Cancer) mutation signatures 3 and 8 associated with homologous recombination (HR) deficiency. In vitro sensitivity of CST cells was tested against 11 chemotherapy agents. Tumors derived from orthotopically injected CST-mCherry cells in FVB-GFP mice showed sensitivity to cisplatin, providing a new model to study the cooperation of BRCA1-KO, mCherry-positive tumor cells and the GFP-expressing stromal compartment in therapy resistance and metastasis formation. In summary, we have established CST cells as a new model recapitulating major characteristics of BRCA1-negative breast cancers
Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells
Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this study, the function of Tks4 was investigated in HCT116 colon cancer cells by knocking the protein out using the CRISPR/Cas9 system. Surprisingly, the absence of Tks4 induced significant changes in cell morphology, motility, adhesion and expression, and localization of E-cadherin, which are all considered as hallmarks of EMT. In agreement with these findings, the marked appearance of fibronectin, a marker of the mesenchymal phenotype, was also observed in Tks4-KO cells. Analysis of the expression of well-known EMT transcription factors revealed that Snail2 was strongly overexpressed in cells lacking Tks4. Tks4-KO cells showed increased motility and decreased cell-cell attachment. Collagen matrix invasion assays demonstrated the abundance of invasive solitary cells. Finally, the reintroduction of Tks4 protein in the Tks4-KO cells restored the expression levels of relevant key transcription factors, suggesting that the Tks4 scaffold protein has a specific and novel role in EMT regulation and cancer progression