Hck Inhibitors as Potential Therapeutic Agents in Cancer and HIV Infection

Musumeci, Francesca; Schenone, Silvia; Brullo, Chiara; Desogus, Andrea; Botta, Lorenzo; Tintori, Cristina

doi:10.2174/0929867322666150209152057

Cited by 16 publications

(10 citation statements)

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“…Therefore, inhibition of p38 MAPK represents a promising strategy for attenuating skin cancer. The roles of Hck and Blk in cancers have been investigated [ 26 – 32 ]. Knocking down Hck substantially enhanced killing of cancer cells by the drug, SS1P, which is a recombinant immunotoxin (RIT) that targets mesothelin in mesothelin-transfected A431 cells [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase

Kim

Lee

et al. 2016

Oncotarget

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Bakuchiol is a meroterpene present in the medicinal plant Psoralea corylifolia, which has been traditionally used in China, India, Japan and Korea for the treatment of premature ejaculation, knee pain, alopecia spermatorrhea, enuresis, backache, pollakiuria, vitiligo, callus, and psoriasis. Here, we report the chemopreventive properties of bakuchiol, which acts by inhibiting epidermal growth factor (EGF)-induced neoplastic cell transformation. Bakuchiol also decreased viability and inhibited anchorage-independent growth of A431 human epithelial carcinoma cells. Bakuchiol reduced A431 xenograft tumor growth in an in vivo mouse model. Using kinase profiling, we identified Hck, Blk and p38 mitogen activated protein kinase (MAPK) as targets of bakuchiol, which directly bound to each kinase in an ATP-competitive manner. Bakuchiol also inhibited EGF-induced signaling pathways downstream of Hck, Blk and p38 MAPK, including the MEK/ERKs, p38 MAPK/MSK1 and AKT/p70S6K pathways. This report is the first mechanistic study identifying molecular targets for the anticancer activity of bakuchiol and our findings indicate that bakuchiol exhibits potent anticancer activity by targeting Hck, Blk and p38 MAPK.

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Section: Discussionmentioning

confidence: 99%

Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase

Kim

Lee

et al. 2016

Oncotarget

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“…Several scaffolds for targeted HCK inhibition are in development based on prior work implicating HCK in the pathogenesis of several solid and hematologic malignancies, as well as productive HIV infection. 41,42 In addition to inhibiting other SRC family members, dasatinib also shows potent inhibition of HCK and may be active in diseases dependent on mutated MYD88. 43 In conclusion, our findings suggest that HCK is a downstream target of mutated MYD88, is activated by IL-6, and triggers pro-survival signaling including PI3K/AKT, MAPK/ERK, and BTK in MYD88-mutated cells.…”

Section: Cc-292mentioning

confidence: 99%

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

Yang

Buhrlage

et al. 2016

Blood

115

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Key Points• HCK transcription and activation is triggered by mutated MYD88, and is an important determinant of pro-survival signaling.• HCK is also a target of ibrutinib, and inhibition of its kinase activity triggers apoptosis in mutated MYD88 cells.Activating mutations in MYD88 are present in ∼95% of patients with Waldenström macroglobulinemia (WM), as well as other B-cell malignancies including activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). In WM, mutated MYD88 triggers activation of Bruton tyrosine kinase (BTK). Ibrutinib, a pleiotropic kinase inhibitor that targets BTK, is highly active in patients with mutated MYD88. We observed that mutated MYD88 WM and ABC DLBCL cell lines, as well as primary WM cells show enhanced hematopoietic cell kinase (HCK) transcription and activation, and that HCK is activated by interleukin 6 (IL-6). Over-expression of mutated MYD88 triggers HCK and IL-6 transcription, whereas knockdown of HCK reduced survival and attenuated BTK, phosphoinositide 3-kinase/ AKT, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling in mutated MYD88 WM and/or ABC DLBCL cells. Ibrutinib and the more potent HCK inhibitor A419259, blocked HCK activation and induced apoptosis in mutated MYD88 WM and ABC DLBCL cells. Docking and pull-down studies confirmed that HCK was a target of ibrutinib. Ibrutinib and A419259 also blocked adenosine triphosphate binding to HCK, whereas transduction of mutated MYD88 expressing WM cells with a mutated HCK gatekeeper greatly increased the half maximal effective concentration for ibrutinib and A419259. The findings support that HCK expression and activation is triggered by mutated MYD88, supports the growth and survival of mutated MYD88 WM and ABC DLBCL cells, and is a direct target of ibrutinib. HCK represents a novel target for therapeutic development in MYD88-mutated WM and ABC DLBCL, and possibly other diseases driven by mutated MYD88. (Blood. 2016;127(25):3237-3252)

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“…Furthermore, current evidence indicates a strong role for Nef:Hck in HIV pathogenesis in vivo, and highlights Hck as an optimal target for pharmacological intervention in the clinic. The nature of different Hck inhibitors and their potential as therapeutic agents for HIV infection is of great current interest in the field and has been recently reviewed in [ 221 ].…”

Section: Manipulation Of the Actin Cytoskeletonmentioning

confidence: 99%

All-Round Manipulation of the Actin Cytoskeleton by HIV

Stella¹,

Turville

2018

Viruses

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While significant progress has been made in terms of human immunodeficiency virus (HIV) therapy, treatment does not represent a cure and remains inaccessible to many people living with HIV. Continued mechanistic research into the viral life cycle and its intersection with many aspects of cellular biology are not only fundamental in the continued fight against HIV, but also provide many key observations of the workings of our immune system. Decades of HIV research have testified to the integral role of the actin cytoskeleton in both establishing and spreading the infection. Here, we review how the virus uses different strategies to manipulate cellular actin networks and increase the efficiency of various stages of its life cycle. While some HIV proteins seem able to bind to actin filaments directly, subversion of the cytoskeleton occurs indirectly by exploiting the power of actin regulatory proteins, which are corrupted at multiple levels. Furthermore, this manipulation is not restricted to a discrete class of proteins, but rather extends throughout all layers of the cytoskeleton. We discuss prominent examples of actin regulators that are exploited, neutralized or hijacked by the virus, and address how their coordinated deregulation can lead to changes in cellular behavior that promote viral spreading.

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Hck Inhibitors as Potential Therapeutic Agents in Cancer and HIV Infection

Cited by 16 publications

References 0 publications

Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase

Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase

HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib

All-Round Manipulation of the Actin Cytoskeleton by HIV

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