Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

Chou, Yi Sheng; Yen, Chueh Chuan; Chen, Wei Ming; Lin, Yung Chan; Wen, Yao Shan; Wei, Ke; Wang, Jir You; Liu, Chun Yu; Yang, Muh Hwa; Chen, Tain Hsiung; Liu, Chien Lin

doi:10.3892/ijo.2016.3352

Cited by 36 publications

(22 citation statements)

References 41 publications

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“…STK899704 treatment increased p53, phosphorylated p53, p21, and p27 levels ( Figure 5A ), which may be due to the decrease in cyclin A level and G 2 /M phase arrest because of tubulin aggregation. These data supported already reported results regarding on the causes of senescence ( Roninson et al, 2001 ; Tierno et al, 2009 ; Chou et al, 2016 ). Also, β-Galactosidase staining showed that STK899704 induced senescence in A549 cells compared with that in control cells.…”

Section: Discussionsupporting

confidence: 93%

The Novel Small Molecule STK899704 Promotes Senescence of the Human A549 NSCLC Cells by Inducing DNA Damage Responses and Cell Cycle Arrest

et al. 2018

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The novel synthetic compound designated STK899704 (PubChem CID: 5455708) suppresses the proliferation of a broad range of cancer cell types. However, the details of its effect on lung cancer cells are unclear. We investigated the precise anticancer effect of STK899704 on senescence and growth arrest of A549 human non-small cell lung cancer (NSCLC) cells. STK899704 affected NSCLC cell cycle progression and decreased cell viability in a dose-dependent manner. Immunofluorescence staining revealed that STK899704 destabilized microtubules. Cell cycle analysis showed an increase in the population of NSCLC cells in the sub-G1 and G2/M phases, indicating that STK899704 might cause DNA damage via tubulin aggregation. Furthermore, we observed increased mitotic catastrophe in STK899704-treated cells. As STK899704 led to elevated levels of the p53 pathway-associated proteins, it would likely affect the core DNA damage response pathway. Moreover, STK899704 promoted senescence of NSCLC cells by inducing the p53-associated DNA damage response pathways. These findings suggest that the novel anti-proliferative small molecule STK899704 promotes cell death by inducing DNA damage response pathways and senescence after cell cycle arrest, being a potential drug for treating human lung cancers.

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Section: Discussionsupporting

confidence: 93%

The Novel Small Molecule STK899704 Promotes Senescence of the Human A549 NSCLC Cells by Inducing DNA Damage Responses and Cell Cycle Arrest

et al. 2018

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“…We tried to elucidate the underlying molecular mechanisms of the synergism of PLK1 inhibitors with paclitaxel and found that the combined treatment causes strong growth inhibition and mitotic arrest, which triggers activation of caspase-3 and apoptosis; these results correlate with previous findings [36,41]. Recently, Noack et al identified a synthetic lethality between volasertib and paclitaxel in ovarian cancer cell lines with CCNE1-amplification, demonstrating that the combination induces a prolonged mitotic arrest and cell death, shifting the balance between pro-and anti-apoptotic proteins toward cell death [42].…”

Section: Discussionsupporting

confidence: 73%

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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“…A number of studies have shown that inhibiting PLK1 expression or function by RNAi or small molecule inhibitors was effective in control of cancer cell proliferation [38], [50], [108], [109].…”

Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

362

269

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Polo-like kinase 1 (PLK1) plays an important role in the initiation, maintenance, and completion of mitosis. Dysfunction of PLK1 may promote cancerous transformation and drive its progression. PLK1 overexpression has been found in a variety of human cancers and was associated with poor prognoses in cancers. Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis. Thus, PLK1 is expected to be a potential target for cancer therapy. In this article, we examined PLK1’s structural characteristics, its regulatory roles in cell mitosis, PLK1 expression, and its association with survival prognoses of cancer patients in a wide variety of cancer types, PLK1 interaction networks, and PLK1 inhibitors under investigation. Finally, we discussed the key issues in the development of PLK1-targeted cancer therapy.

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Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

Cited by 36 publications

References 41 publications

The Novel Small Molecule STK899704 Promotes Senescence of the Human A549 NSCLC Cells by Inducing DNA Damage Responses and Cell Cycle Arrest

The Novel Small Molecule STK899704 Promotes Senescence of the Human A549 NSCLC Cells by Inducing DNA Damage Responses and Cell Cycle Arrest

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

PLK1, A Potential Target for Cancer Therapy

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