Inhibition of tumor growth and angiogenesis of tamoxifen‑resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor

Kim, Ji Won; Gautam, Jaya; Kim, Jung‐Ae; Kang, Keon Wook

doi:10.3892/ol.2019.10059

Cited by 39 publications

(44 citation statements)

References 57 publications

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“…The JAK1/2-selective inhibitor ruxolitinib is FDA approved for the treatment of polycythemia vera, myelofibrosis, and graft versus host disease, and it has been shown to decrease STAT3 activation in preclinical models of several solid tumors [18,22,65] . Ruxolitinib inhibited STAT3 activation and decreased cell growth in breast cancer [66,67] , NSCLC [68] , HNC [69] , esophageal cancer [70] , bladder cancer [71] , HCC [72] , cervical cancer [73] , and colorectal cancer [74,75] cell lines. In pancreatic cancer cells, ruxolitinib treatment was also shown to decrease expression of pro-angiogenic genes and impede epithelial-to-mesenchymal transition [76,77] .…”

Section: Ruxolitinibmentioning

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: Ruxolitinibmentioning

confidence: 99%

Targeting the JAK/STAT pathway in solid tumors

Qureshy¹,

Johnson²,

Grandis³

2020

JCMT

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“…The classical JAK2 inhibitor is known as AG490. Recently, ruxolitinib is found to have a potential to be a new selective JAK2 inhibitor and to block STAT3 activation [94]. Furthermore, tagalide A and tagalol A are also found to inhibit the phosphorylation of STAT3 and JAK2 in breast cancer [86].…”

Section: Compounds Inhibiting the Activation Of Stat3 In Breast Cancermentioning

confidence: 99%

Role of STAT3 signaling pathway in breast cancer

2020

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Breast cancer has grown to be the second leading cause of cancer-related deaths in women. Only a few treatment options are available for breast cancer due to the widespread occurrence of chemoresistance, which emphasizes the need to discover and develop new methods to treat this disease. Signal transducer and activator of transcription 3 (STAT3) is an early tumor diagnostic marker and is known to promote breast cancer malignancy. Recent clinical and preclinical data indicate the involvement of overexpressed and constitutively activated STAT3 in the progression, proliferation, metastasis and chemoresistance of breast cancer. Moreover, new pathways comprised of upstream regulators and downstream targets of STAT3 have been discovered. In addition, small molecule inhibitors targeting STAT3 activation have been found to be efficient for therapeutic treatment of breast cancer. This systematic review discusses the advances in the discovery of the STAT3 pathways and drugs targeting STAT3 in breast cancer.

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“…5 Moreover, it has been demonstrated that PIM inhibitors can enhance the efficacy of existing PCa treatments, which will be discussed further, including radiotherapy, 10 chemotherapy, 9 and androgen deprivation. 59 PIM co-targeting could also reduce patient mortality by potentiating the antimetastatic effects of other treatments, including strategies targeting the PI3K pathway 60,61 or JAK/STAT pathway 62,63 or anti-androgen therapy. 64 PIM AND THE PI3K PATHWAY The PI3K/AKT/mTOR pathway has been shown to contribute to the development of all hallmarks of cancer and is frequently disrupted in cancer.…”

Section: Pim Inhibition Within the Prostate Cancer Clinical Pathwaymentioning

confidence: 99%

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for cotargeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.

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Inhibition of tumor growth and angiogenesis of tamoxifen‑resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor

Cited by 39 publications

References 57 publications

Targeting the JAK/STAT pathway in solid tumors

Targeting the JAK/STAT pathway in solid tumors

Role of STAT3 signaling pathway in breast cancer

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

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