Tubulin‐targeting agent combination therapies: dosing schedule could matter

Solary, Éric

doi:10.1111/bph.12101

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…Various groups reported that the use of vincristine combined with anthracyclines significantly reduced the antitumor effects, as compared with the administration of each drug alone [ 31 – 33 ]. In accordance with these results, we also found antagonistic activity between STK405759 and doxorubicin [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

STK405759 as a combination therapy with bortezomib or dexamethasone, in in vitro and in vivo multiple myeloma models

et al. 2018

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Multiple myeloma (MM) remains an incurable hematological malignancy. Combination regimens of conventional and novel drugs have improved patient’s survival. However, most patients inevitably relapse and become refractory to the current therapeutic armamentarium.We investigated the efficacy of combining the microtubule-targeting agent STK405759 with dexamethasone or bortezomib in vitro and in vivo.STK405759 combined with dexamethasone or bortezomib had synergistic cytotoxic activity in RPMIS, CAG and MM1.S human MM cell lines through activation of caspase 2, 3, 8, 9 and PARP. These treatments remained cytotoxic in the presence of bone marrow stroma cells. In other MM cells, including cells resistant to vincristine, melphalan, mitoxantrone or dexamethasone, these combinations decreased significantly survival as compared to single agents.In in vivo studies, STK405759 disrupted existing blood vessels in xenograft tumors, acting not only as a cytotoxic agent but also as an anti-angiogenic drug. Mice treated with STK405759 in combination with dexamethasone or bortezomib resulted in greater tumor growth inhibition, increased overall response and prolonged survival as compared to as compared to BTZ or DEXA alone. Their anticancer activity was mediated by activation of apoptosis and reduction of tumor microvessel density.These preclinical studies provide the rationale for future clinical trials of STK405759, dexamethasone and bortezomib combinations to improve the outcome of multiple myeloma patients.

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Section: Discussionmentioning

confidence: 99%

STK405759 as a combination therapy with bortezomib or dexamethasone, in in vitro and in vivo multiple myeloma models

et al. 2018

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Virtual and experimental high throughput screening of substituted hydrazones on β-Tubulin polymerization

Xavier

Jayabalan

Ragavendran

et al. 2021

Bioorganic Chemistry

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Copper-Catalyzed Syntheses of Pyrene-Pyrazole Pharmacophores and Structure Activity Studies for Tubulin Polymerization

et al. 2018

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Tubulin polymerization is critical in mitosis process, which regulates uncontrolled cell divisions. Here, we report a new class of pyrene-pyrazole pharmacophore (PPP) for targeting microtubules. Syntheses of seven pyrenyl-substituted pyrazoles with side-chain modification at N-1 and C-3 positions of the pyrazole ring were accomplished from alkenyl hydrazones via C–N dehydrogenative cross-coupling using copper catalyst under aerobic condition. Tubulin polymerization with PPPs was investigated using docking and biological tools to reveal that these ligands are capable of influencing microtubule polymerization and their interaction with α-, β-tubulin active binding sites, which are substituent specific. Furthermore, cytotoxicity response of these PPPs was tested on cancer cells of different origin, such as MCF-7, MDA-MB231, and C32, and also noncancerous normal cells, such as MCF-10A. All newly synthesized PPPs showed excellent anticancer activities. The anticancer activities and half-maximal inhibitory concentration (IC50) values of all PPPs across different cancer cell lines (MCF-7, MDA-MB231, and C32) have been demonstrated. 1,3-Diphenyl-5-(pyren-1-yl)-1H-pyrazole was found to be best among all other PPPs in killing significant population of all of the cancerous cell with IC50 values 1 ± 0.5, 0.5 ± 0.2, and 5.0 ± 2.0 μM in MCF-7, MDA-MB231, and C32 cells, respectively.

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Tubulin‐targeting agent combination therapies: dosing schedule could matter

Cited by 3 publications

References 10 publications

STK405759 as a combination therapy with bortezomib or dexamethasone, in in vitro and in vivo multiple myeloma models

STK405759 as a combination therapy with bortezomib or dexamethasone, in in vitro and in vivo multiple myeloma models

Virtual and experimental high throughput screening of substituted hydrazones on β-Tubulin polymerization

Copper-Catalyzed Syntheses of Pyrene-Pyrazole Pharmacophores and Structure Activity Studies for Tubulin Polymerization

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