New Inhibitors of Polo-like Kinase 1 Function and Their Emerging Role in Attenuating Tumor Growth in Systemic Malignancies

December 2012 | Volume 11 | Issue 12 | Editorials | 1402 | Copyright © December 2012


Shailendra Kapoor MD

University of Illinois at Chicago, Chicago, IL

Abstract
The recent article by de Oliveira et al1 was highly interesting and thought provoking. Interestingly, the past few years have seen the identification of a number of new inhibitors of polo-like kinase 1 (PLK1) function.
For instance, BI 2536 is a relatively new PLK1inhibitor. In squamous cell carcinomas of the head and neck, BI 2536 administration causes apoptosis and inhibits proliferation.2 BI 2536 also inhibits tumor growth in neurological tumors such as glioblastoma multiforme.3 At the same time, it reduces SOX2 expression in these tumors. The radiosensitivity of certain tumors to ionizing radiation is enhanced by pretreatment with BI 2536.4 This is especially true in medulloblastomas. BI 2536 also enhances the potency of agents such as 5-fluorouracil in solid tumors such as cholangio-carcinomas.5 Leukopenia, anorexia, and hypertension are some of the dose-limiting side effects of BI 2536.
Another new PLK1 inhibitor is rigosertib. When used in conjunction with chemotherapeutic agents such as gemcitabine, rigosertib has shown antiproliferative activity and attenuation of tumor growth in lymphoproliferative malignancies such as Hodgkin lymphomas.6 Similar effects have been observed in pancreatic ductal adenocarcinomas.
NMS-P937 is another new PLK1 inhibitor. It shows synergistic activity with chemotherapeutic agents such as irinotecan in tumors such as colorectal carcinomas7 and exhibits significant antiproliferative activity when used in conjunction with cytarabine in hematologic malignancies such as acute myeloid leukemia.
Another emerging PLK1 inhibitor is TAK-960, which has demonstrated broad-spectrum efficacy against a number of solid tumors, such as colorectal carcinomas, including those that express multidrug-resistant protein 1.8 It has also demonstrated efficacy against certain leukemias. The fact that TAK-960 is orally available makes it an ideal PLK1 inhibitor.
Another emerging orally available PLK1 inhibitor that has shown promise in gastrointestinal tumors models such as human colon tumor (HT29) xenograft models is MLN0905.9 In addition, GW843682X has shown marked promise against pediatric malignancies.10
Similarly, PLK1 inhibitor in tumors such as hepatocellular carcinomas can be achieved by transfection with adenovirus coding for anti-PLK1 short-hairpin RNA. Certain flavonoids such as biochanin A also accentuate apoptosis in tumors by upregulating p21 expression and thereby subsequently inhibiting PLK1 transcription.11
The above examples clearly illustrate the amazing potential of PLK1 inhibition and the need to identify further inhibitors of PLK1 function.

Disclosures

The author has no relevant conflicts of interest to disclose.

References

  1. de Oliveira JC, Brassesco MS, Pezuk JA, et al. In vitro PLK1 inhibition by BI 2536 decreases proliferation and induces cell-cycle arrest in melanoma cells. J Drugs Dermatol. 2012;11(5):587-592.
  2. Wagenblast J, Hirth D, Thron L, et al. Effects of the Polo-like-kinase-1-in-hibitor BI2536 in squamous cell carcinoma cell lines of the head and neck. Oncol Lett. 2012;4(1):175-177.
  3. Lee C, Fotovati A, Triscott J, et al. Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice. Stem Cells. 2012;30(6):1064-1075.
  4. Harris PS, Venkataraman S, Alimova I, et al. Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells. BMC Cancer. 2012;12:80.
  5. Thrum S, Lorenz J, MÖssner J, Wiedmann M. Polo-like kinase 1 inhibition as a new therapeutic modality in therapy of cholangiocarcinoma. Anticancer Res. 2011;31(10):3289-3299.
  6. Ma WW, Messersmith WA, Dy GK, et al. Phase I study of Rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer. Clin Cancer Res. 2012;18(7):2048-2055.
  7. Valsasina B, Beria I, Alli C, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012;11(4):1006-1016.
  8. Hikichi Y, Honda K, Hikami K, et al. TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum pre-clinical antitumor activity in multiple dosing regimens. Mol Cancer Ther. 2012;11(3):700-709.
  9. Duffey MO, Vos TJ, Adams R, et al. Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905). J Med Chem. 2012;55(1):197-208.
  10. Spaniol K, Boos J, Lanvers-Kaminsky C. An in-vitro evaluation of the polo-like kinase inhibitor GW843682X against paediatric malignancies. Anti-cancer Drugs. 2011;22(6):531-542.
  11. Seo YJ, Kim BS, Chun SY, Park YK, Kang KS, Kwon TG. Apoptotic effects of genistein, biochanin-A and apigenin on LNCaP and PC-3 cells by p21 through transcriptional inhibition of polo-like kinase-1. . J Korean Med Sci. 2011;26(11):1489-1494.

AUTHOR CORRESPONDENCE

Shailendra Kapoor MDshailendrakapoor@yahoo.com
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