Fig 8. Proposed mechanisms of the combinatorial effects of curcumin with DFMO or BENSpm.

Treatment with curcumin alone down regulates the biosynthetic enzymes ODC and SamDC, while up regulating SMOX. The result is decreased putrescine and the conversion of spermine back to spermidine. SSAT activity is lowered, likely due to the decrease in spermine. (A) Adding DFMO further inhibits ODC, reducing the spermidine generated through biosynthesis. Compensatory uptake of polyamines from the extracellular environment would likely be increased by both DFMO and curcumin. (B) Uptake of BENSpm through the polyamine transporter is stimulated by the curcumin-mediated decrease in biosynthesis. BENSpm induces catabolism through SSAT, thereby increasing the depletion of spermine and catabolizing the spermidine accumulated by the induction of SMOX by curcumin. As no accumulation of putrescine is evident, the acetylated polyamines are presumably exported from the cell.