Blood, 15 February 2003, Vol. 101, No. 4, pp. 1210-1210
PS-341: prospecting a new hope for myeloma
In this issue, Hideshima and colleagues (page 1530)
define the intracellular effects of the proteasome inhibitor PS-341
(Millennium Pharmaceuticals, Cambridge, MA) on myeloma cells.
This drug has shown promising activity in early clinical trials
for relapsing myeloma patients. Moreover, recent laboratory studies
show that exposure to this agent may greatly increase the sensitivity
of highly chemotherapy-resistant myeloma cells to the cytotoxic effects of chemotherapy, and have led to clinical trials exploiting this effect
for myeloma patients. PS-341 reduces the DNA-binding activity of the
transcription factor nuclear factor-kappa B (NF-
B) by reducing the
degradation of the NF-B inhibitor, IB. In support of this,
expression of a dominant-negative vector of IB that is resistant to
proteasome-mediated degradation induces apoptosis in both
chemotherapy-sensitive and -resistant myeloma cells.
But recent studies, including the Hideshima paper, suggest that other
effects of PS-341 may contribute to its antimyeloma effects. This
drug has profound effects on TNF, JNK activities, p53, MDM2, DNA
protein kinase catalytic subunit (DNA-PKcs), and the ATM proteins.
Specifically, exposure to this drug inhibits XIAP, a gene
activated by NF-B. This results in enhanced JNK activity,
leading to caspase-mediated apoptosis. Other studies have shown that
the enhancement of JNK activity by PS-341 is associated with increased
TNF production. Indeed, inhibition of TNF reduces the antitumor effects
of PS-341. Moreover, this induction of JNK activity also results in
activation of caspase-3, leading to cleavage of DNA repair
enzymes including DNA-PKcs and ATM, resulting in impaired DNA repair.
The proteasome inhibitor also increases p53, resulting in induction of
MDM2 expression, as well as enhanced association of these 2 proteins.
Ultimately, the activation of caspase-3 leads to p53 phosphorylation
and MDM2 degradation, resulting in activation of p53. Thus, the
proapoptotic activities of PS-341 on multiple intracellular signaling
pathways in myeloma cells results in its potent antitumor effects.
Importantly, furthering our understanding of the intracellular
antimyeloma effects of PS-341 will help lead to the development of
other drugs that more specifically target these pathways and the
exploration of new drug combinations with the potential for enhanced
clinical benefits.
James R. Berenson
Cedars-Sinai Medical Center; UCLA School of
Medicine
