Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma.
High-risk multiple myeloma can be correlated with amplification and overexpression of the cell cycle regulator CKS1B. Herein, we used the COMPARE algorithm to correlate high expression of CKS1B mRNA in the NCI-60 cell line panel with the concentration causing 50% growth inhibition (GI(50)) of >40,000 synthetic compounds. This led to the identification of NSC 338258 (EPED3), a highly stable, hydrophilic derivative of the plant alkaloid ellipticine. In vitro, this synthetic anticancer compound exhibits dramatic cytotoxic activity against myeloma cells grown in suspension or in coculture with stromal cells. EPED3-induced cell cycle arrest and an apoptotic progression that appear to be a consequence of the instantaneous effect of the drug on cytoplasmic organelles, particularly mitochondria. Disruption of mitochondria and cytoplasmic distribution of cytochrome c initiated the intracellular proteolytic cascade through the intrinsic apoptotic pathway. EPED3 is able to induce apoptosis in myeloma cells with de novo or acquired resistance to commonly administered antimyeloma agents. Collectively, our data suggest that EPED3 targets mitochondrial function to rapidly deplete chemical energy and initiate apoptosis in myeloma cells at nanomolar concentrations while leaving stromal cells unharmed.
Tian
Erming
E
The Donna D and Donald M Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Landowski
Terry H
TH
Stephens
Owen W
OW
Yaccoby
Shmuel
S
Barlogie
Bart
B
Shaughnessy
John D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004611:Ellipticines / Q000494:pharmacology / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
C529584:9-(dimethylaminoethoxy)ellipticine; D000970:Antineoplastic Agents; C093090:CKS1B protein, human; D002352:Carrier Proteins; D004611:Ellipticines; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases