New Antimitotic Agents with Activity in Multi-Drug-Resistant Cell Lines and in Vivo Efficacy in Murine Tumor Models

2001 ◽  
Vol 44 (25) ◽  
pp. 4416-4430 ◽  
Author(s):  
Bruce G. Szczepankiewicz ◽  
Gang Liu ◽  
Hwan-Soo Jae ◽  
Andrew S. Tasker ◽  
Indrani W. Gunawardana ◽  
...  
Keyword(s):  
Cell Lines ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Tumor Models ◽  
In Vivo Efficacy ◽  
Murine Tumor ◽  
Drug Resistant Cell

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.

scholarly journals Ad-VT enhances the sensitivity of chemotherapy-resistant lung adenocarcinoma cells to gemcitabine and paclitaxel in vitro and in vivo

2022 ◽  
Author(s):  
Gaojie Song ◽  
Chao Shang ◽  
Lili Sun ◽  
Yiquan Li ◽  
Yilong Zhu ◽  
...  
Keyword(s):  
Cell Lines ◽  
A549 Cells ◽  
Resistance Index ◽  
Tumor Model ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Chemotherapeutic Drugs ◽  
Drug Resistant Cell

SummaryBackground One of the main challenges in the clinical treatment of lung cancer is resistance to chemotherapeutic drugs. P-glycoprotein (P-gp)-mediated drug resistance is the main obstacle to successfully implementing microtubule-targeted tumor chemotherapy. Purpose In this study, we explored the effect of Ad-hTERTp-E1a-Apoptin (Ad-VT) on drug-resistant cell lines and the molecular mechanism by which Ad-VT combined with chemotherapy affects drug-resistant cells and parental cells. Methods In vitro, cell proliferation, colony formation, resistance index (RI), apoptosis and autophagy assays were performed. Protein expression was analyzed by Western blotting. Finally, a xenograft tumor model in nude mice was used to detect tumor growth and evaluate histological characteristics. Results Our results showed that Ad-VT had an obvious killing effect on A549, A549/GEM and A549/Paclitaxel cancer cells, and the sensitivity of drug-resistant cell lines to Ad-VT was significantly higher than that of parental A549 cells. Compared with A549 cells, A549/GEM and A549/Paclitaxel cells had higher autophagy levels and higher viral replication ability. Ad-VT decreased the levels of p-PI3k, p-Akt and p-mTOR and the expression of P-gp. In vivo, Ad-VT combined with chemotherapy can effectively inhibit the growth of chemotherapy-resistant tumors and prolong the survival of mice. Conclusions Thus, the combination of Ad-VT and chemotherapeutic drugs will be a promising strategy to overcome chemoresistance.

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

scholarly journals Berberine reduces temozolomide resistance by inducing autophagy via the ERK1/2 signaling pathway in glioblastoma

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Huiling Qu ◽  
Xiaofu Song ◽  
Zhuyin Song ◽  
Xin Jiang ◽  
Xin Gao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cell Lines ◽  
Therapeutic Agent ◽  
Chemotherapeutic Agent ◽  
Experimental System ◽  
Resistant Cell ◽  
Isoquinoline Alkaloid ◽  
Therapeutic Resistance ◽  
In Vivo Efficacy

Abstract Background The ability to treat glioblastoma (GBM) using the chemotherapeutic agent temozolomide (TMZ) has been hampered by the development of therapeutic resistance. In this study, we assessed the ability of the isoquinoline alkaloid berberine to alter GBM TMZ resistance using two different TMZ-resistant cell lines to mimic a physiologically relevant GBM experimental system. Methods By treating these resistant cell lines with berberine followed by TMZ, we were able to assess the chemosensitivity of these cells and their parental strains, based on their performance in the MTT and colony formation assays, as well as on the degree of detectable apoptosis that was detected in the strains. Furthermore, we used Western blotting to assess autophagic responses in these cell lines, and we extended this work into a xenograft mouse model to assess the in vivo efficacy of berberine. Results Through these experiments, our findings indicated that berberine enhanced autophagy and apoptosis in TMZ-resistant cells upon TMZ treatment in a manner that was linked with ERK1/2 signaling. Similarly, when used in vivo, berberine increased GBM sensitivity to TMZ through ERK1/2 signaling pathways. Conclusions These findings demonstrate that berberine is an effective method of increasing the sensitization of GBM cells to TMZ treatment in a manner that is dependent upon the ERK1/2-mediated induction of autophagy, thus making berberine a potentially viable therapeutic agent for GBM treatment.

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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