The novel Janus kinase inhibitor ruxolitinib confers protection against carbon tetrachloride-induced hepatotoxicity via multiple mechanisms

Hazem, Sara H.; Shaker, Mohamed E.; Ashamallah, Sylvia A.; Ibrahim, Tarek M.

doi:10.1016/j.cbi.2014.06.017

Cited by 18 publications

(12 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, preclinical experiments have shown that treatment with ruxolitinib, a JAK1/2 inhibitor, prevented liver toxicity in mice treated with known hepatotoxic agents. 28,29 Although the possibility that JAK inhibition exerts a hepatoprotective effect is interesting, this finding may instead reflect divergent populations or other factors related to prior treatment or histology.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phillips

Forero‐Torres

Sher

et al. 2018

Blood

View full text Add to dashboard Cite

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination pneumonia (n = 5), pneumonia (unrelated to; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phillips

Forero‐Torres

Sher

et al. 2018

Blood

View full text Add to dashboard Cite

show abstract

“…TNF-α, IL-1β, and IL-6 are critical cytokines in inflammatory responses, and their levels are increased during the development of liver damage [13]. TNF-α, which is produced by Kupffer cells, can induce immune responses by activating T cells and macrophages and further stimulate the secretion of other inflammatory cytokines and the production of NO [22]. IL-1β is another proinflammatory cytokine playing a vital role in the regulation of hepatic NO synthesis [23].…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective effect of Coreopsis tinctoria flowers against carbon tetrachloride-induced liver damage in mice

Tsai

Chiu

Chen

et al. 2017

BMC Complement Altern Med

View full text Add to dashboard Cite

show abstract

“…The IL-10 level in the hepatic supernatant of SD rats with CCl 4 -induced liver injury did not change in response to treatment with ginseng extract and ginsenoside Rb1 for two weeks, although CCl 4 injection alone induced a slight decrease in their level [ 57 ]. However, the IL-10 level in the serum of Balb/c mice with CCl 4 -induced liver injury was significantly reduced by pretreatment with ruxolitinib (15 mg/kg) for 2 h, whereas the levels in the CCl 4 injected group were higher than in the control group [ 58 ]. In this study, the expression of IL-10 was dramatically enhanced by GEGR pretreatment in a dose dependent manner, which differed from the results of previous studies.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Gallotannin-Enriched Extract Isolated from Galla Rhois against CCl4-Induced Hepatotoxicity in ICR Mice

Kim

Koh

et al. 2016

Nutrients

View full text Add to dashboard Cite

To investigate the toxicity, protective effects, and action mechanism of gallotannin-enriched extracts isolated from Galla Rhois (GEGR) against carbon tetrachloride (CCl4)-induced hepatotoxicity in Institute for Cancer Research (ICR) mice, alterations in serum biochemical indicators, histopathological structure, antioxidative status, hepatic apoptosis-related proteins, and liver fibrosis regulating factors were measured in mice pretreated with GEGR for five days before CCl4 injection. The GEGR/CCl4 treated group showed decreased levels of three serum marker enzymes (ALP, AST, and ALT) representing liver toxicity, although LDH levels remained constant. Necrotic area indicating hepatic cell death significantly inhibited, while malondialdehyde (MDA) concentration and superoxide dismutase (SOD) expression were dramatically recovered in the GEGR preadministrated group. In mechanism analyses of GEGR, the formation of active caspase-3 and enhancement of Bax/Bcl-2 expression was effectively inhibited in the GEGR/CCl4 treated group. The level of pro-inflammatory cytokines, TNF-α and IL-6, as well as the phosphorylation of p38 and JNK in the TNF-α downstream signaling pathway was rapidly recovered in the GEGR/CCl4 treated group, while anti-inflammatory cytokine (IL-10) increased slightly in the same group. Furthermore, the GEGR/CCl4 treated group showed a significant decrease in collagen accumulation results from alleviation of MMP-2 expression, TGF-β1 secretion and the phosphorylation of Smad2/3. Taken together, these results suggest that GEGR may induce remarkable protective effects against hepatic injury induced by CCl4 treatment through upregulation of the anti-inflammatory and antioxidant system.

show abstract

The novel Janus kinase inhibitor ruxolitinib confers protection against carbon tetrachloride-induced hepatotoxicity via multiple mechanisms

Cited by 18 publications

References 52 publications

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

Hepatoprotective effect of Coreopsis tinctoria flowers against carbon tetrachloride-induced liver damage in mice

Protective Effect of Gallotannin-Enriched Extract Isolated from Galla Rhois against CCl4-Induced Hepatotoxicity in ICR Mice

Contact Info

Product

Resources

About