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-κB) by reducing the degradation of the NF-κB inhibitor, IκB. In support of this, expression of a dominant-negative vector of IκB 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-κB. 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.

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