PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer

Martino, Daniela De; Yilmaz, Emrullah; Orlacchio, Arturo; Ranieri, Michela; Zhao, Kunpeng; Cristofano, Antonio Di

doi:10.1016/j.canlet.2018.09.024

Cited by 19 publications

(16 citation statements)

References 58 publications

(64 reference statements)

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“…The latter data reinforce the potentiality of the combination between PLK1 inhibitors and the class of anti-mitotic drugs. The synergistic activity of PLK1 and PI3K inhibition combination has been recently reported in anaplastic thyroid cancer models and was likely to be due to a reducing mitotic slippage and endoreduplication [48]. Finally, considering that PLK1 inhibitor shows activity also in HGSOC, the combination of PLK1 inhibitor and paclitaxel could represent a new option also in this setting, particularly in platinum refracting or relapsing tumors.…”

Section: Discussionmentioning

confidence: 64%

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Affatato

Carrassa

Chilà

et al. 2020

Cancers

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Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

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Section: Discussionmentioning

confidence: 64%

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Affatato

Carrassa

Chilà

et al. 2020

Cancers

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“…It is intriguing to determine which cellular signaling pathway mediates HIV-1–induced PLK1 elevation. It has been reported that PLK1 cross-talks with the phosphoinositide 3-kinase (PI3K) pathway, which mutually affect each other’s activity ( 31 , 32 ), and that the combinatory inhibition of PLK1 and PI3K is an encouraging anticancer therapy ( 33 ). We first examined whether PI3K is required for HIV-1–induced PLK1 elevation by using three PI3K inhibitors, LY294002, wortmannin, and 3-methyladenine (3-MA).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

et al. 2020

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Although combination antiretroviral therapy is effective in controlling HIV-1 infection, latent HIV-1 proviruses cannot be eliminated. HIV-1 reactivation induced by the mere use of latency-reversing agents is insufficient to render death of reservoir cells, indicating that certain intrinsic survival mechanisms exist. We report that Polo-like kinase 1 (PLK1) plays a critical role in survival of CD4+ T cells that undergo HIV-1 reactivation from latency or de novo infection. PLK1 is elevated in both scenarios, which requires HIV-1 Nef. HIV-1 enhances PLK1 SUMOylation, causing its nuclear translocation and protein stabilization. Inhibition or knockdown of PLK1 markedly facilitates death of HIV-1-infected CD4+ T cells. Furthermore, PLK1 inhibitors strikingly reduce the size of HIV-1 latent reservoirs in primary CD4+ T cells. Our findings demonstrate that HIV-1 infection hijacks PLK1 to prevent cell death induced by viral cytopathic effects, and that PLK1 is a promising target for chemical “killing” of HIV-1 reservoir cells.

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“…Apoptosis of ZT55-treated cells was assessed by FACS analysis after staining with Annexin-V and propidium iodide (PI) [18]. HEL cells (10 6 cells/ml) were treated for 24, 48 or 72 h with different concentrations of ZT55 (0, 12.5, 25, or 50 μM).…”

Section: Methodsmentioning

confidence: 99%

Discovery and evaluation of ZT55, a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms

Chen

Yang

et al. 2019

J Exp Clin Cancer Res

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BackgroundThe JAK2-STAT signaling pathway plays a critical role in myeloproliferative neoplasms (MPN). An activating mutation in JAK2 (V617F) is present in ~ 95% of polycythemia vera, essential thrombocythemia, and primary myelofibrosis cases. This study aims to explore the selective JAK2V617F inhibitor, evaluate the efficacy and possible mechanism of ZT55 on MPN.MethodsHTRF assays were conducted to evaluate the selective inhibition of ZT55 for JAKs. Cell apoptosis, proliferation, and cycle arrest assays were performed to examine the effect of ZT55 on HEL cell line with JAK2V617F mutation in vitro. Western analysis was used to monitor the expression and activity of proteins on JAK2/STAT pathway. A mice xenograft model was established to evaluate the antitumor efficacy of ZT55 in vivo. Peripheral blood samples from patients with the JAK2V617F mutation were collected to estimate the effect of ZT55 on erythroid colony formation by colony-forming assay.ResultsWe found that ZT55 showed a selective inhibition of a 0.031 μM IC50 value against JAK2. It exhibited potent effects on the cellular JAK-STAT pathway, inhibiting tyrosine phosphorylation in JAK2V617F and downstream STAT3/5 transcription factors. ZT55 inhibited the proliferation of the JAK2V617F-expressing HEL cell line, leading to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis. Notably, ZT55 also significantly suppressed the growth of HEL xenograft tumors in vivo. Further evaluation indicated that ZT55 blocked erythroid colony formation of peripheral blood hematopoietic progenitors from patients carrying the JAK2V617F mutation.ConclusionThese results suggest that ZT55 is a highly-selective JAK2 inhibitor that can induce apoptosis of human erythroleukemia cells by inhibiting the JAK2-STAT signaling.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1062-x) contains supplementary material, which is available to authorized users.

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PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer

Cited by 19 publications

References 58 publications

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo

Discovery and evaluation of ZT55, a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms

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PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer

Cited by 19 publications

References 58 publications

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 + T cells ex vivo

Discovery and evaluation of ZT55, a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms

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Inhibition of Polo-like kinase 1 (PLK1) facilitates the elimination of HIV-1 viral reservoirs in CD4 ⁺ T cells ex vivo