scholarly journals Drug combinations as effective anti-leishmanials against drug resistant Leishmania mexicana

2020 ◽  
Vol 11 (8) ◽  
pp. 905-912
Author(s):  
Humera Ahmed ◽  
Charlotte R. Curtis ◽  
Sara Tur-Gracia ◽  
Toluwanimi O. Olatunji ◽  
Katharine C. Carter ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Cell Lines ◽  
Resistant Cell ◽  
Drug Combinations ◽  
Drug Resistant ◽  
Leishmania Mexicana

Synergistic and antagonist drug interactions of drug combinations against Leishmania drug sensitive and resistant cell lines.

scholarly journals α-Difluoromethylornithine-resistant cell lines obtained after one-step selection of Leishmania mexicana promastigote cultures

1997 ◽  
Vol 324 (3) ◽  
pp. 847-853 ◽  
Author(s):  
Cecilia P. SÁNCHEZ ◽  
Juan MUCCI ◽  
Nélida S. GONZÁLEZ ◽  
Alberto OCHOA ◽  
Mario M. ZAKIN ◽  
...  
Keyword(s):  
Cell Lines ◽  
Specific Activity ◽  
Synthetic Medium ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Morphological Transformation ◽  
Irreversible Inhibitor ◽  
Step Selection

Proliferation of Leishmania mexicana promastigotes in synthetic medium can be blocked by the depletion of intracellular polyamine pools induced by the presence of d,l-α-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase (ODC). Here we report that DFMO-resistant cell lines growing normally at DFMO levels of 10 mM have been obtained from non-proliferating cultures after a single-step selection in the presence of high concentrations of the drug. The DFMO-resistant promastigotes underwent a morphological transformation into an ‘amastigote-like’ form after incubation for several hours at gradually increasing temperatures up to 35 °C. The uptake of DFMO was not significantly altered in the drug-resistant cell lines but in both cases (promastigote and ‘amastigote-like’ forms) the ODC specific activity was increased approx. 15-fold over the normal enzymic levels found in the wild-type Leishmania. The enzyme affinities for its substrate and for DFMO gave very similar values in the drug-resistant promastigotes and the wild-type parasites. In contrast, ODC from the ‘amastigote-like’Leishmania showed a higher affinity for ornithine and a decreased capacity for the binding of DFMO. An 80-fold amplification of the ODC gene and a corresponding increase in its transcripts have been detected in both DFMO-resistant Leishmania cell lines. The drug-resistant phenotypes with their characteristic morphologies, the increased levels of ODC activity and the amplification of the ODC gene have been stable for at least 6 months in the absence of selective pressure.

scholarly journals The significance of lumican expression in ovarian cancer drug-resistant cell lines

Oncotarget ◽  
2017 ◽  
Vol 8 (43) ◽  
pp. 74466-74478 ◽  
Author(s):  
Andrzej Klejewski ◽  
Karolina Sterzyńska ◽  
Karolina Wojtowicz ◽  
Monika Świerczewska ◽  
Małgorzata Partyka ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Resistant Cell ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Drug Resistant Cell

scholarly journals Abstract No. 448 Comparison of electrochemotherapy and radiation for chemosensitization of drug resistant cell lines

2018 ◽  
Vol 29 (4) ◽  
pp. S190
Author(s):  
L. Vroomen ◽  
W. Vista ◽  
M. Fuijmori ◽  
J. Humm ◽  
S. Solomon ◽  
...  
Keyword(s):  
Cell Lines ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Drug Resistant Cell

Novel Targeting Of Phospho-Marcks Overcomes Drug Resistance and Induces Anti-Tumor Activity In Preclinical Models Of Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 282-282 ◽  
Author(s):  
Yijun Yang ◽  
Manujendra N Saha ◽  
Yan Chen ◽  
Lugui Qiu ◽  
Donna E Reece ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cell Lines ◽  
Research Funding ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Sensitive Cell ◽  
Bortezomib Treatment ◽  
Cell Cycle Pathway ◽  
Rpmi 8226

Abstract Multiple myeloma (MM) remains incurable due to the development of a drug-resistant phenotype after prolonged therapy. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a protein kinase C (PKC) substrate that plays an important role in cell adhesion, spreading and invasion. Our previous studies found that overexpression of phospho-MARCKS (pMARCKS) was detected in developed drug resistant MM cell lines (RPMI-8226 R5, MM.1R) relative to their parental drug sensitive cell lines (RPMI-8226S, MM.1S). We hypothesized that pMARCKS is involved in chemo- and novel drug resistance in MM. To further evaluate the drug resistance, we exposed both RPMI-8226 R5 and MM.1R cell lines to varying dosages of bortezomib, dexamethasone, doxorubicin, and lenalidomide. By MTT assay, both resistant cell lines were found to have significantly higher viability to all 4 drugs compared to their respective non-resistant lines. In addition, Western blot analysis showed increased pMARCKS expressions in all 3 bortezomib resistant cell lines 8226.BR, OPM2.BR, and ANBL-6.BR as compared to their respective bortezomib sensitive cell lines. We next acquired MM patient samples collected at diagnosis and at relapse after bortezomib treatment, and investigated their pMARCKS expression with immunoblotting analyses. The patient samples collected from relapse after bortezomib treatment had higher pMARCKS expression than those collected at diagnosis. Furthermore, we studied additional 3 primary MM patient samples with high pMARCKS expressions and 3 with low expressions for their vaibility after a 36 hour bortezomib treatment, and found that the samples with high pMARCKS expressions were more resistant to bortezomib than those with low pMARCKS expressions (mean IC50 of 7.1 nM and mean IC50 of 4.8 nM, respectively; p = 0.042). Importantly, combination of a low dosage of bortezomib (5.0 nM) with either 2.5 uM or 5.0 uM of enzastaurin (an inhibitor of phospho-PKC), displayed a synergistic cytotoxicity on myeloma cells with high pMARCKS expressions. To further elucidate the role of pMARCKS in drug resistance, we knocked down pMARCKS expression by transfecting siMARCKS into 8226 R5 and MM.1R cells. Following the knockdown, both cell lines had significantly lower viability after treatment with either bortezomib, dexamethasone, doxorubicin, or lenolidomide, in comparison to empty vector controls. FACS analysis and annexin V assay of the knockdown cells and the control cells from both cell lines showed significantly induction of G1/S cell cycle arrest and apoptosis in the knockdown cells. The immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) DNA-qPCR analysis further demonstrated that pMARCKS regulates SKP2 expression through binding with E2F1, mediating SKP2/p27Kip1 cell cycle pathway. Finally, we investigated the effect of inhibition of pMARCKS in a 8226 R5 xenograft model of SCID mice. Mice injected with shMARCKS-transfected 8226 R5 cells and received bortezomib showed significant retardation of tumor growth and prolonged survival compared to the control groups. Taken together, our data indicate that pMARCKS is constitutively activated in resistant and relapsed MM cells and contributes to drug resistance by regulating E2F1 mediated SKP2/p27Kip1 cell cycle pathway, thus providing a preclinical rationale for targeting pMARCKS as a promising approach in patients with refractory/relapsed MM. Disclosures: Reece: BMS: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Millennium: Research Funding; Novartis: Honoraria; Onyx: Honoraria.

Next Generation XPO1 Inhibitor KPT-8602 for the Treatment of Drug-Resistant Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1818-1818 ◽  
Author(s):  
Joel G Turner ◽  
Jana L Dawson ◽  
Christopher L Cubitt ◽  
Erkan Baluglo ◽  
Steven Grant ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Ex Vivo ◽  
Single Agent ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
Induced Apoptosis ◽  
Drug Resistant Cell

Abstract Purpose Human multiple myeloma (MM) remains an incurable disease despite relatively effective treatments, including proteasome inhibitors, immunomodulator-based therapies, and high-dose chemotherapy with autologous stem cell rescue. New agents are needed to further improve treatment outcomes. In previous studies, we have shown that inhibitors of the nuclear export receptor XPO1, in combination with bortezomib, carfilzomib, doxorubicin, or melphalan, synergistically induced apoptosis in MM cells in vitro, in vivo and ex vivo without affecting non-myeloma cells. In early clinical trials, the oral, brain penetrating XPO1 inhibitor selinexor showed clear anti-myeloma activity however adverse events have been recorded, including nausea and anorexia. Our purpose was to investigate the use of oral KPT-8602, a novel small-molecule inhibitor of XPO1 with minimal brain penetration, which has been shown to have reduced toxicities in rodents and primates while maintaining potent anti-tumor effects. Experimental Procedures To test the efficacy of KPT-8602, we treated human MM cell lines (both parental and drug-resistant) with KPT-8602 ± currently used MM drugs, including bortezomib, carfilzomib, dexamethasone, doxorubicin, lenalidomide, melphalan, topotecan, and VP-16. Human MM cell lines assayed included RPMI-8226 (8226), NCI-H929 (H929), U266, and MM1.S, PI-resistant 8226-B25 and U266-PSR, doxorubicin-resistant 8226-Dox6 and 8226-Dox40, and melphalan-resistant 8226-LR5 and U266-LR6 cell lines. MM cells (2-4x106 cells/mL) were treated for 24 hours with KPT-8602 (300 nM), followed by treatment with one of the listed anti-MM agents for an additional 24 hours. MM cells were then assayed for cell viability (CellTiter-Blue, Promega). In addition, cells were treated with KPT-8602 ± anti-MM agents concurrently for 20 hours and assayed for apoptosis by flow cytometry. In vivo testing was done in NOD/SCID-g mice by intradermal injection of U266 MM cells. Treatment started 2 weeks after tumor challenge with KPT-8602 (10 mg/kg) ± melphalan (1 or 3 mg/kg) 2X/week (Tuesday, Friday) or with KPT-8602 alone 5X weekly (10 mg/kg) (Monday-Friday). A parallel experiment was run using the clinical XPO1 inhibitor KPT-330 (selinexor). Ex vivo testing was performed on MM cells from newly diagnosed/relapsed patient bone marrow aspirates with KPT-8602 ± bortezomib, carfilzomib, dexamethasone, doxorubicin, lenalidomide, melphalan, topotecan, or VP16. CD138+/light-chain+ cells were assayed for apoptosis by flow cytometry. Results Viability assay showed that KPT-8602 had low IC50values (~140 nM) as a single agent and functioned synergistically with bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16. (CI values < 1.0). This synergistic effect was less pronounced in myeloma cells when KPT-8602 was used in combination with dexamethasone or lenalidomide. KPT-8602 ± bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 combination therapy also induced apoptosis in all MM cell lines tested, including drug-resistant cell lines, as shown by caspase 3 cleavage and flow cytometric analyses. NOD/SCID-gamma mouse tumor growth was reduced and survival increased in KPT-8602/melphalan-treated mice when compared to single-agent controls. In addition, mice treated with KPT-8602 5X weekly had significantly reduced tumor growth and increased survival when compared to 2X weekly drug administration. No toxicity was observed in KPT-8602-treated mice as determined by weight loss in both the 2X and 5X groups. In patient bone marrow biopsies, the combination of KPT-8602 ± bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 was more effective than single agents at inducing apoptosis in CD138+/LC+ MM cells in both newly diagnosed and relapsed/refractory patient samples. Conclusions We found that the novel XPO1 inhibitor KPT-8602 sensitizes MM cells to bortezomib, carfilzomib, doxorubicin, melphalan, topotecan, and VP16 as shown by apoptosis in parental and drug-resistant cell lines and by cell viability assays. Sensitization was found to be synergistic. In addition, KPT-8602 was effective in treatment of human MM tumors in mice as a single agent or in combination with melphalan and was effective when combined with several MM drugs in MM cell lines and MM patient bone marrow aspirates. KPT-8602 may be a potential candidate for future clinical trials. Disclosures Shacham: Karyopharm: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics, Inc.: Employment, Patents & Royalties.

P-gp localization in mitochondria and its functional characterization in multiple drug-resistant cell lines

2006 ◽  
Vol 312 (20) ◽  
pp. 4070-4078 ◽  
Author(s):  
Michela Solazzo ◽  
Ornella Fantappiè ◽  
Nadia Lasagna ◽  
Chiara Sassoli ◽  
Daniele Nosi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Functional Characterization ◽  
Resistant Cell ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Multiple Drug Resistant ◽  
Drug Resistant Cell

Diverse cross-resistance phenotype to ET-743 and PM00104 in multi-drug resistant cell lines

2008 ◽  
Vol 63 (6) ◽  
pp. 1121-1129 ◽  
Author(s):  
Zhenfeng Duan ◽  
Edwin Choy ◽  
Jose Maria Jimeno ◽  
Carmen Del Maria Cuevas ◽  
Henry J. Mankin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Resistance Phenotype ◽  
Drug Resistant Cell
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