Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity.
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.
Humeniuk
R
R
Department 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 08903, USA.
Menon
L G
LG
Mishra
P J
PJ
Saydam
G
G
Longo-Sorbello
G S A
GS
Elisseyeff
Y
Y
Lewis
L D
LD
Aracil
M
M
Jimeno
J
J
Bertino
J R
JR
Banerjee
D
D
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000637:transplantation; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology; D008775:Methylprednisolone / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008942:Mitoxantrone / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010456:Peptides, Cyclic; D013047:Specific Pathogen-Free Organisms; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D003561:Cytarabine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D008942:Mitoxantrone; D008775:Methylprednisolone; C098980:plitidepsin