Ruxolitinib sensitizes ovarian cancer to reduced dose Taxol, limits tumor growth and improves survival in immune competent mice

Reeves, Patrick M.; Abbaslou, Mojgan A.; Kools, Farah R.W.; Vutipongsatorn, Kritchai; Tong, Xiaoyun; Gavegnano, Christina; Schinazi, Raymond F.; Poznansky, Mark C.

doi:10.18632/oncotarget.21541

Cited by 13 publications

(11 citation statements)

References 41 publications

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“…Ruxolitinib in combination with antibodies against cytokines such as IL-6 (tocilizumab) improved survival in mice bearing ovarian cancer tumors. Ruxolitinib in combination with paclitaxel reduced cell proliferation and colony formation in ovarian cancer cell lines and inhibited tumor growth in in vivo models [83,84] . Ruxolitinib has been shown to improve sensitivity to oncolytic viral therapy in HNC [85] , pancreatic cancer [86] , glioblastoma multiforme (GBM) [87] , and NSCLC [88] .…”

Section: Nct01822756mentioning

confidence: 99%

Targeting the JAK/STAT pathway in solid tumors

Qureshy¹,

Johnson²,

Grandis³

2020

JCMT

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Aberrant activation of signal transducer and activator of transcription (STAT) proteins is associated with the development and progression of solid tumors. However, as transcription factors, these proteins are difficult to target directly. In this review, we summarize the role of targeting Janus kinases (JAKs), upstream activators of STATs, as a strategy for decreasing STAT activation in solid tumors. Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation, cell proliferation, and cell survival; in in vivo models, they also inhibit tumor growth. JAK inhibitors, particularly the JAK1/2 inhibitor ruxolitinib, sensitize cell lines and murine models to chemotherapy, immunotherapy, and oncolytic viral therapy. Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors; two of these inhibitors are already Food and Drug Administration (FDA) approved for the treatment of myeloproliferative disorders and rheumatoid arthritis, making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated. Four JAK inhibitors (two of which are FDA approved for other indications) have exhibited promising anti-cancer effects in preclinical studies; however, clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted. In summary, JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.

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Section: Nct01822756mentioning

confidence: 99%

Targeting the JAK/STAT pathway in solid tumors

Qureshy¹,

Johnson²,

Grandis³

2020

JCMT

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“…4, A to C). This dosing range was chosen because doses at 30 to 180 mg/kg have been used for JAK inhibition in mice ( 50 – 54 ), and doses at 60 to 90 mg/kg have been reported to be analogous to the prescribed 20 to 25 mg in humans (see Discussion for limitations) ( 51 – 53 ). Together, our data demonstrate that ruxolitinib can inhibit CaMKII in CMs and functions rapidly in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…Although our in vitro and in cellulo data support that achievable concentrations will have an effect, our in vivo data are based on several assumptions. Dosing at 60 to 90 mg/kg has been previously reported to be analogous to human 20-to 25-mg doses (51)(52)(53), but these studies lack definitive pharmacological data to demonstrate this equivalency. The widely used Nair and Jacob scale (75) estimates that the mouse equivalent of 25 mg is ~5 mg/kg, a dose that is too low for an effect in our hands.…”

Section: Discussionmentioning

confidence: 99%

An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor

et al. 2023

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Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and tractability for high-throughput screening. Using this tool, we carried out a drug repurposing screen (4475 compounds in clinical use) in human cells expressing constitutively active CaMKII. This yielded five previously unrecognized CaMKII inhibitors with clinically relevant potency: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. We found that ruxolitinib, an orally bioavailable and U.S. Food and Drug Administration–approved medication, inhibited CaMKII in cultured cardiomyocytes and in mice. Ruxolitinib abolished arrhythmogenesis in mouse and patient-derived models of CaMKII-driven arrhythmias. A 10-min pretreatment in vivo was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia, a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. At cardioprotective doses, ruxolitinib-treated mice did not show any adverse effects in established cognitive assays. Our results support further clinical investigation of ruxolitinib as a potential treatment for cardiac indications.

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“…Cancer is one of the diseases with a high mortality rate despite applications of various therapeutics. Treatment of intractable cancers is difficult because of tumor heterogeneity, occurrence of drug resistance, lack of target drugs, and so on. − To treat intractable cancers, studies on combinatorial chemotherapies with different anticancer mechanisms have been carried out. − For treatment of triple negative breast cancer (TNBC), there was a study to alter the intrinsic state of the cancer cells by rewiring of oncogenic signaling pathways. As the epidermal growth factor receptor (EGFR) of TNBC cells was inhibited, the rewiring of signaling pathways occurred, and hence, the apoptotic pathways by DNA damage were reactivated. , …”

Section: Introductionmentioning

confidence: 99%

MMP9-Sensitive PEG-Shedding Nanoliposomes for Targeted Codelivery of Erlotinib and Doxorubicin to MDA-MB-231 Cells

Kim

Yoon

Lee

et al. 2021

ACS Appl. Polym. Mater.

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Tumor microenvironment-sensitive nanoliposomes (TMS-NLs) were prepared as triple negative breast cancer (TNBC)-specific carriers for synergistic therapeutics. The NLs shed polyethylene glycol (PEG) by matrix metalloproteinase 9 (MMP9) secreted from the cancer cells, expose a cell-penetrating peptide, the X peptide, and are consequently internalized into syndecan-4 overexpressed by the cancer cells. TMS-NLs containing an unprecedented conjugate, palmitoyl-X-MMP9cleavable peptide (M)-methoxy PEG2000, were prepared and coencapsulated with erlotinib (ERL) and doxorubicin (DOX). Treatment of DOX after ERL represented synergistic cytotoxicity against MDA-MB-231 cells. The X peptide generated from the XMX peptide by MMP9 was internalized into the cancer cells. The ERL and DOX-coencapsulated TMS-NL labeled with Cy5.5 demonstrated internalization of the NL into the cancer cells. ED-TMS-NLs were cytotoxic against MDA-MB-231 cells, not MCF-7 cells. Compared with other ED-NL formulations, the PEG-shedding ED-TMS-NL showed higher cellular uptake and cytotoxicity against MDA-MB-231 cells, as well as DOX transport to the nucleus. In the MDA-MB-231 tumor-xenografted mouse model, the tumor growth inhibition of the ED-TMS-NL was superior to that of the ED-PEGylated-NL. The MMP9-sensitive PEG-shedding and syndecan-4-targeting TMS-NL can be a platform for a TNBC cell microenvironment-sensitive transport system of synergistic therapeutics.

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Ruxolitinib sensitizes ovarian cancer to reduced dose Taxol, limits tumor growth and improves survival in immune competent mice

Cited by 13 publications

References 41 publications

Targeting the JAK/STAT pathway in solid tumors

Targeting the JAK/STAT pathway in solid tumors

An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor

MMP9-Sensitive PEG-Shedding Nanoliposomes for Targeted Codelivery of Erlotinib and Doxorubicin to MDA-MB-231 Cells

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