Interplay between anthracyclines and proteasome inhibitors.
| Pathway . | Anthracyclines . | Proteasome Inhibitors . |
|---|---|---|
| How proteasome inhibitors may enhance the activity of anthracyclines | ||
| DNA damage repair | Act in part by damaging DNA, and their activity would be enhanced if repair functions were inactivated | Repress some of the DNA damage repair enzymes, such as the DNA protein kinase c catalytic subunit |
| NF-κB | Activate NF-κB, which is anti-apoptotic in part through downstream targets such as Bcl-2 and inhibitors of apoptosis | Inhibit NF-κB by stabilizing its inhibitor IκB, thereby enhancing programmed cell death |
| P-glycoprotein | Expression selected by prior anthracyclines; acts to reduce intracellular anthracycline levels | Block maturation of P-glycoprotein, leading to accumulation of inactive precursors |
| How anthracyclines may enhance the activity of proteasome inhibitors | ||
| MKP-1 | Inhibit MKP-1 through repression of its promoter, augmenting JNK activity and apoptosis | Induce MKP-1, which is anti-apoptotic through its inhibition of JNK phosphorylation and activation |
| Pathway . | Anthracyclines . | Proteasome Inhibitors . |
|---|---|---|
| How proteasome inhibitors may enhance the activity of anthracyclines | ||
| DNA damage repair | Act in part by damaging DNA, and their activity would be enhanced if repair functions were inactivated | Repress some of the DNA damage repair enzymes, such as the DNA protein kinase c catalytic subunit |
| NF-κB | Activate NF-κB, which is anti-apoptotic in part through downstream targets such as Bcl-2 and inhibitors of apoptosis | Inhibit NF-κB by stabilizing its inhibitor IκB, thereby enhancing programmed cell death |
| P-glycoprotein | Expression selected by prior anthracyclines; acts to reduce intracellular anthracycline levels | Block maturation of P-glycoprotein, leading to accumulation of inactive precursors |
| How anthracyclines may enhance the activity of proteasome inhibitors | ||
| MKP-1 | Inhibit MKP-1 through repression of its promoter, augmenting JNK activity and apoptosis | Induce MKP-1, which is anti-apoptotic through its inhibition of JNK phosphorylation and activation |