1. ¹Department of Medicine and Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA
2. ²Department of Pharmacology, Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA
3. ³Section of Clinical Pharmacology, Department of Medicine, Dartmouth Medical School and Dartmouth Hitchcock Medical Center, Lebanon, NH, USA
4. ⁴PharmaMar R&D, Madrid, Spain

Correspondence: Dr D Banerjee, Department of Medicine and Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, UMDNJ, 195 Little Albany Street, New Brunswick, NJ 08903, USA. E-mail: banerjed@umdnj.edu

⁵Present address: LG Menon, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, USA.

⁶Present address: G Saydam, Department of Hematology, Ege University Medical School, Izmir, Turkey.

⁷Present address: GSA Longo-Sorbello, Department of Hematology, Centro di Riferimento Oncologico, Taormina, Italy.

Received 15 December 2006; Revised 18 July 2007; Accepted 24 July 2007; Published online 23 August 2007.

Abstract

Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G₁ and G₂ phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.