Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin

Wong, John; Smith, Logan B.; Magun, Eli; Engstrøm, Thomas; Kelley-Howard, Kirsten; Jandhyala, Dakshina M.; Thorpe, Cheleste M.; Magun, Bruce E.; Wood, Lisa J.

doi:10.4161/cbt.22628

Cited by 59 publications

(65 citation statements)

References 42 publications

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“…Sorafenib 46 inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and is clinically used to treat renal cell carcinoma, hepatocellular carcinoma, and thyroid carcinoma. We have previously shown that all three of these tyrosine kinase inhibitors block the expression of inflammatory genes by BMDM following exposed to doxorubicin 34 . In the presence of these inhibitors, the expression of RNA encoding IL-1β, IL-6, and CXCL-1 by doxorubicin, vincristine, or both was blocked (Fig.…”

Section: Resultsmentioning

confidence: 78%

“…Bacterial pore-forming toxins, bacterial and viral pathogens, asbestos, silica, ATP, double-stranded RNA, uric acid crystals, and translation inhibitors (such as emetine and ribotoxic stressors including doxorubicin) stimulate IL-1β processing via the NLRP3-inflammasome. Of cancer chemotherapeutic agents, gemcitabin and 5-FU have been shown to activate the inflammasome in myeloid-derived suppressor cells; 40 doxorubicin has been shown to do the same in macrophages 34 , 41 …”

Section: Introductionmentioning

confidence: 99%

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Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs

Wong

Trần

Magun

et al. 2014

Cancer Biology & Therapy

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Cytotoxic chemotherapeutic drugs, especially when used in combination, are widely employed to treat a variety of cancers in patients but often lead to serious symptoms that negatively affect physical functioning and quality of life. There is compelling evidence that implicates cytotoxic chemotherapy-induced inflammation in the etiology of these symptoms. Because IL-1β plays a central role as an initiator cytokine in immune responses, we compared doxorubicin, a drug known to induce IL-1β production, with ten other commonly prescribed chemotherapeutic drugs in their ability to lead to processing and secretion of IL-1β by primary mouse macrophages. Seven of them (melphalan, cisplatin, vincristine, etoposide, paclitaxel, methotrexate, and cytarabine) caused the production of IL-1β in cells pretreated with lipopolysaccharide. When delivered in combination with doxorubicin, one of the drugs, vincristine, was also capable of synergistically activating the NLRP3-dependent inflammasome and increasing expression of IL-1β, IL-6, and CXCL1. The absence of TNF-α and IL-1 signaling caused a partial reduction in the production of mature IL-1β. Three small-molecule inhibitors known to suppress activity of kinases situated upstream of mitogen-activated kinases (MAPKs) inhibited the expression of IL-1β, IL-6, and CXCL1 when doxorubicin and vincristine were used singly or together, so specific kinase inhibitors may be useful in reducing inflammation in patients receiving chemotherapy.

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Section: Resultsmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs

Wong

Trần

Magun

et al. 2014

Cancer Biology & Therapy

Self Cite

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“…ZAK is critically important for JNK activation upstream of MKK4 and MKK7(28) and is important for doxorubicin-induced apoptosis(29, 30). TAOK2 has been implicated to be an activator of JNK as well(31–35).…”

Section: Resultsmentioning

confidence: 99%

Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

Vin

Ching

Ojeda

et al. 2014

Molecular Cancer Therapeutics

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Sorafenib is FDA-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5–10% rate of developing cutaneous squamous cell carcinoma/keratoacanthomas. Paradoxical activation of ERK in BRAF-wild-type cells has been implicated in RAF-inhibitor-induced cSCC. Here we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting JNK activation through the off-target inhibition of ZAK kinase. Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

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“…Evidences are accumulating regarding a potential anti-inflammatory effect of nilotinib in different experimental models [19,24,47]. Herein, nilotinib's ability to reduce oxidative stress, boost host antioxidant defense mechanism and immune system, and reduce expression Fig.…”

Section: Discussionmentioning

confidence: 96%

Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib

2015

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Diabetes mellitus is an ever growing world-wide health problem. The patient has to stick to a firm life-long therapeutic regimen, otherwise diabetic complications will develop. Diabetic nephropathy (DN) is one of the most common diabetic complications and it requires careful medical attendance. Nilotinib hydrochloride is a protein tyrosine kinase inhibitor reported to have numerous therapeutic efficacies besides being an anticancer. In the current study, single I.P. streptozotocin (50 mg/kg) injection was used to induce type I diabetes mellitus in male Sprague-Dawley rats. After 8 weeks, significant deterioration of renal function with urinary excretion of nephrin, podocalyxin, and albumin was observed. Daily oral administration of nilotinib (20 mg/kg) for 8 weeks significantly improved signs of DN on all investigated scales. On a biochemical scale, kidney functions, albuminuria, urinary nephrin, podocalyxin excretion, and host oxidant/antioxidant balance significantly improved. Kidney content of nitric oxide, expression of toll-like receptors 4 and NF-κB/p65 activity significantly declined as well. On a histopathological scale, α-smooth muscle actin and nestin expression significantly declined. Meanwhile, area of fibrosis significantly declined as seen with significant reduction in accumulation of extracellular matrix components and kidney content of collagen. Ultimately, such improvements were accompanied by significant restoration of normal kidney physiology and function. In conclusion, nilotinib can hinder progression of DN through various mechanisms. Reduction of oxidative stress, enhancement of host antioxidant defense system, reduction of inflammation, angiogenesis, tissue hypoxia, and pro-fibrogenic biomarker expression can be implicated in the beneficial therapeutic outcome observed with nilotinib therapy.

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Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin

Cited by 59 publications

References 42 publications

Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs

Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs

Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib

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