PLK1 is a critical determinant of tumor cell sensitivity to CPT11 and its inhibition enhances the drug antitumor efficacy in squamous cell carcinoma models sensitive and resistant to camptothecins.

Valentina Zuco,Nadia Zaffaroni,Michelandrea De Cesare,Giuliana Cassinelli,Cinzia Lanzi

doi:10.18632/oncotarget.3538

Valentina Zuco, Nadia Zaffaroni + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.3538

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Journal: Oncotarget	Publication Date: Mar 12, 2015
Citations: 59	License type: cc-by

Affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori

Abstract

Intrinsic and acquired tumor drug resistance limits the therapeutic efficacy of camptothecins (CPTs). Downregulation of the mitotic kinase PLK1 was found associated with apoptosis induced by SN38 (CPT11 active metabolite). We investigated the role of PLK1 in the cell response to CPTs in squamous cell carcinoma (SCC) and pediatric sarcoma cell lines and explored the therapeutic potential of the combination of CPT11 and the PLK1 inhibitor BI2536 in CPT-sensitive and -resistant tumor models. Gain- and loss-of-function experiments established a direct role for PLK1 in counteracting SN38 antiproliferative and pro-apoptotic effects. The ability to activate an efficient G2/M cell cycle checkpoint allowing PLK1 ubiquitination and degradation was found associated with SN38-induced apoptosis in SCC cells. However, the synergistic interaction between SN38 and BI2536 enhanced apoptosis in cell lines both sensitive and resistant to SN38-induced apoptotic cell death. A well-tolerated CPT11/BI2536 cotreatment resulted in improved antitumor effect against SCC xenografts in mice compared to single agent treatments. The increased apoptosis induction was reflected in a high rate of complete responses and cures in mice harboring SCC, including tumors with intrinsic or acquired resistance to CPTs. PLK1 inhibition represents a promising strategy to improve the antitumor efficacy of CPT11-based regimens.

Highlights

Camptothecin (CPT) derivatives are potent cytotoxic drugs that have shown clinical activity in a variety of human tumors
We examined the effect of treatment with SN38, the active metabolite of CPT11, in squamous cell carcinoma (SCC) cell lines previously characterized for sensitivity to the CPTs [24, 25]
Loss of Polo-like kinase 1 (PLK1) was observed after exposure to SN38 in CaSki cells, sensitive to CPT-induced apoptosis, and not in SiHa cells which are intrinsically resistant to SN38-induced apoptotic cell death as evidenced by Tunel assay performed on both SCC cell lines after treatment at equitoxic and equimolar concentrations

Summary

Introduction

Camptothecin (CPT) derivatives are potent cytotoxic drugs that have shown clinical activity in a variety of human tumors. CPT11, which functions as a pro-drug requiring conversion to the active metabolite SN38 by plasma and cellular carboxylesterases, is used in gastrointestinal malignancies [1, 2]. CPTs are usually administered in combination with other agents and the discovery of new rational combinatorial strategies continues to be a goal in the effort to optimize the treatment therapeutic efficacy [3]. CPTs share with other cytotoxic drugs doselimiting toxicities, which may prevent the use of effective doses. Additional limitations to the clinical efficacy of CPTs are related to tumor intrinsic and acquired drug resistance, which represent the main cause of therapeutic failure [2, 4]

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