An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies

Abstract

Polo-like kinase 1 (PLK1) is a regulator of mitosis and its upregulation in tumours is often associated with poor prognosis. Although PLK1 inhibitors have already entered phase 1 clinical trials, little is known about their impact on the treatment of paediatric malignancies. Thus, we evaluated the concept of PKL1 inhibition by testing the effects of the PLK1 inhibitor GW843682X alone and in combination with the topoisomerase 1 inhibitor, camptothecin, against a panel of 18 paediatric tumour cell lines. Cytotoxicity was evaluated by MTT test and by caspase 3/7 activation. Expression of target was confirmed by western blot analysis. Expression of ATP binding cassette transporters was analysed by quantitative real-time reverse transcription PCR. GW843682X significantly inhibited cell growth in all 18 cell lines. Concentrations, which inhibited cell growth by 50% compared with untreated controls after 72 h, ranged from 0.02 to 11.7 μmol/l. Apart from the N-Myc-amplified neuroblastoma cell lines, the osteosarcoma cell lines MNNG-HOS and OST, which are highly resistant to standard anticancer drugs, were sensitive to GW843682X. The toxicity of GW843682X was dependent neither on the ATP binding cassette drug transporter expression nor on the p53 mutation status. Neither synergistic nor antagonistic effects were observed for the combination of GW843682X and camptothecin in 14 cell lines. GW843682X showed considerable toxicity against a panel of paediatric tumour cell lines suggesting that PLK1 inhibitors under clinical development should be evaluated against paediatric malignancies too.

Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children

“…None of these trials have specifically addressed the possibility that PLK1 inhibitors may be beneficial for the treatment of brain tumors. Our group has demonstrated that PLK1 inhibitors could be used to target glioblastoma (18,40) and another group has published data agreeing with our findings in medulloblastoma (41,42). We illustrate that PLK1 is a promising drug target for medulloblastoma because (i) it is highly expressed in tumors relative to normal brain tissues and (ii) there are small molecule inhibitors that suppress primary medulloblastoma cells and cell lines in vitro and in vivo.…”

Targeting polo-like kinase 1 by NMS-P937 in osteosarcoma cell lines inhibits tumor cell growth and partially overcomes drug resistance

“…According to this assumption, PLKs-targeting drugs, namely BI 2536 [10] and GW843682X [11], have demonstrated interesting activities in some human OS cell lines. BI 2536 also proved to inhibit in vivo growth in mouse OS xenografts [9].…”

“…Few data so far reported on PLK1 and its inhibitor drugs in OS suggest that targeting this kinase may be a valuable approach [8] and that PLK1 inhibitors are able to decrease tumor cell growth [9][10][11]. However, further indications are needed to confirm these assumptions.…”

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

“…Combination therapy of cytarabine and NMS-P937 markedly increased survival of mice first injected with primary AML cells. 24,43 Also, a combination of vincristine, which was shown to increase PLK1 protein levels in an AML cell line, and GW843682X synergistically inhibited growth and induced apoptosis in leukemia cells in vitro. 22 These findings encourage further exploration of the efficacy of both PLK1-targeting monotherapy and combination therapy in a clinical setting.…”

“…[9][10][11][12][13][14][15][16][17][18][19][20] PLK1 has been extensively studied in solid tumors, but more recent reports show elevated PLK1 expression in adult leukemias. [21][22][23] The PLK1/PLK3 inhibitor GW843682X displayed in vitro toxicity to a panel of pediatric cancer cell lines, 24 but no PLK1-specific inhibitor has yet entered clinical trials in pediatric malignancies. Identification of a common tumor-driving gene may allow the development of therapeutics that are applicable to different types of cancer patients.…”