Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Nair, Jayasree S.; Schwartz, Gary K.

doi:10.1080/15384101.2015.1078033

Cited by 11 publications

(14 citation statements)

References 37 publications

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“…The same study found that aberrant spindle accumulation was apparent with higher doses of Tak960. Another study demonstrated that Tak960 causes an induction of apoptosis, possibly due to a down regulation of Mcl-1 in sarcoma cells (75). Another Plk1 inhibitor, NMS-P937, has shown notable success in the reduction of osteosarcoma tumor growth (76).…”

Section: Plk1 As a Drug Targetmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

338

272

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Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor, volasertib, has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed towards understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer.

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Section: Plk1 As a Drug Targetmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

338

272

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“…3 ). Recent studies have shown Plk1 and Phospho-Plk1 accumulation upon exposure to Plk1 inhibition by TAK-960 and CBB2001, respectively [ 33 , 34 ]. At early time points, Plk1 levels remained constant in both sensitive and resistant cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown TAK-960 is an effective anti-proliferative agent in in vitro models of ovarian, colorectal, sarcoma, breast, and non-small cell lung cancers, among others [ 18 , 33 , 44 ]. We report TAK-960 exposure has a pronounced anti-proliferative effect on CRC cell lines and IC 50 is independent of common CRC driver mutations, including KRAS and p53 as previously reported [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recent work in sarcoma cell lines shows Plk1 inhibition by TAK-960 leads to polyploidy, cell cycle arrest, and apoptosis as methods of tumor suppression. Furthermore, tumor suppression by either cell cycle arrest or apoptosis was cell line specific [ 33 ]. Consistent with these data, we observed a marked increase in polyploidy with TAK-960 treatment, however, this effect was seen in sensitive (HCT116 and WIDR) as well as resistant (DLD1) cell lines.…”

Section: Discussionmentioning

confidence: 99%

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Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer

Klauck¹,

Bagby

Capasso³

et al. 2018

BMC Cancer

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BackgroundPolo-like kinase 1 (Plk1) is a serine/threonine kinase that is a key regulator of multiple stages of mitotic progression. Plk1 is upregulated in many tumor types including colorectal cancer (CRC) and portends a poor prognosis. TAK-960 is an ATP-competitive Plk1 inhibitor that has demonstrated efficacy across a broad range of cancer cell lines, including CRC. In this study, we investigated the activity of TAK-960 against a large collection of CRC models including 55 cell lines and 18 patient-derived xenografts.MethodsFifty-five CRC cell lines and 18 PDX models were exposed to TAK-960 and evaluated for proliferation (IC50) and Tumor Growth Inhibition Index, respectively. Additionally, 2 KRAS wild type and 2 KRAS mutant PDX models were treated with TAK-960 as single agent or in combination with cetuximab or irinotecan. TAK-960 mechanism of action was elucidated through immunoblotting and cell cycle analysis.ResultsCRC cell lines demonstrated a variable anti-proliferative response to TAK-960 with IC50 values ranging from 0.001 to > 0.75 μmol/L. Anti-proliferative effects were sustained after removal of drug. Following TAK-960 treatment a highly variable accumulation of mitotic (indicating cell cycle arrest) and apoptotic markers was observed. Cell cycle analysis demonstrated that TAK-960 treatment induced G2/M arrest and polyploidy. Six out of the eighteen PDX models responded to single agent TAK-960 therapy (TGII< 20). The addition of TAK-960 to standard of care chemotherapy resulted in largely additive antitumor effects.ConclusionTAK-960 is an active anti-proliferative agent against CRC cell lines and PDX models. Collectively, these data suggest that TAK-960 may be of therapeutic benefit alone or in combination with other agents, although future work should focus on the development of predictive biomarkers and hypothesis-driven rational combinations.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4036-z) contains supplementary material, which is available to authorized users.

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“…First, we analyzed C1qbp expression because a previous study showed that C1qbp promotes cellular proliferation and resistance to cell death in breast cancer cell lines 25 . Second, we analyzed Mcl-1 expression because a previous study reported that Mcl-1 suppression was related to apoptosis caused by PLK1 inhibition in sarcomas 26 . In the sequencing data, C1qbp mRNA expression decreased depending on PLK1 knockdown (Fig.…”

Section: Resultsmentioning

confidence: 99%

Decreased KPNB1 Expression is Induced by PLK1 Inhibition and Leads to Apoptosis in Lung Adenocarcinoma

2017

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Lung cancer is a major cause of death worldwide, with lung adenocarcinoma being the most frequently diagnosed subtype in Japan. Finding the target of an anticancer drug can improve lung adenocarcinoma treatments. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in mitotic progression, and PLK1 inhibition induces cell cycle arrest and apoptosis in tumor cells. In addition, a variety of PLK1 inhibitors have been identified for cancer treatments. In this study, we looked for the target gene of the anticancer drug that has synergy with PLK1 inhibitors. We identified karyopherin beta 1 (KPNB1) as a possible target for lung adenocarcinoma treatment. We found that PLK1 inhibition decreased KPNB1 expression in lung adenocarcinoma cells and KPNB1 depletion inhibited cell proliferation via apoptosis. The same apoptosis signaling pathway may be activated because the expression of common apoptosis-related genes was decreased by PLK1 and KPNB1 silencing; however, the time course of cell growth inhibition was somewhat different. Cell cycle analysis showed that KPNB1 depletion increased the proportion of cells at the G0/G1 phase, although cells also accumulated at the G2/M phase in PLK1-depleted cells. Our findings suggest that decreased KPNB1 expression may be associated with the apoptosis induced by PLK1 inhibition.

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Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Cited by 11 publications

References 37 publications

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Antitumor activity of the polo-like kinase inhibitor, TAK-960, against preclinical models of colorectal cancer

Decreased KPNB1 Expression is Induced by PLK1 Inhibition and Leads to Apoptosis in Lung Adenocarcinoma

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