Serine Threonine Protein Phosphatase Inhibitors with Antitumor Activity

R. E. Honkanen

Department of Biochemistry and Molecular Biology, University of South Alabama, MSB 2362, College of Medicine, Mobile, AL 36688, USA [email protected]

1 Introduction 296

1.1 Target Phosphatases for Drug Development 297

2 Cantharidin 298

2.1 Molecular Mechanism of Action 299

2.2 Effects of Cantharidin on Cells 300

2.3 Clinical Use of Cantharidin 302

2.4 Toxicity 302

3 Fostriecin 303

3.1 Molecular Mechanism of Action 303

3.2 Inhibition of Cell Cycle Progression 304

3.3 Inhibition of Topoisomerase II Activity 305

3.4 Inhibition of Protein Phosphatase Activity 306

3.5 Cellular Uptake of Fostriecin 307

3.6 Effects of Fostriecin on Cells 308

3.7 Human Clinical Trials and Plasma Pharmacokinetics 309

3.7.1 Stability of Fostriecin 310

3.7.2 Pharmacokinetics in Rabbits 310

3.7.3 Pharmacokinetics in Humans 310

3.8 Toxicity Studies 311

3.8.1 Toxicity in Rodents 311

3.8.2 Toxicity in Humans 312

4 Conclusions 313

References 313

Abstract Recent studies with fostriecin and derivatives of cantharidin suggest that the development of specific, or highly selective, inhibitors of serine/threonine protein phosphatases, notably PP2A, PP4, and PP5, may prove useful for the medical management of human cancer. This chapter will review the discovery and development of natural compounds that were originally shown to have marked antitumor activity and subsequently found to act as potent inhibitors of certain PPP-family phosphatases. The review will focus on two compounds, cantharidin and fostriecin, addressing discovery, molecular mechanisms of action, affects on cultured cell, clinical use, toxicity, plasma pharmacokinetics, and a brief review of data from a phase I human clinical trial.

Keywords Fostriecin ■ Cantharidin ■ Phosphatase ■ Inhibitor ■ Tumor ■ Human ■ Serine

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