A novel natural compound, a cycloanthranilylproline derivative (Fuligocandin B), sensitizes leukemia cells to apoptosis induced by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) through 15-deoxy-Δ12, 14 prostaglandin J2 production

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells; however, not all human tumors respond to TRAIL, potentially limiting its therapeutic utility. Although there is substantial evidence that cytotoxic drugs can augment sensitivity to TRAIL, it has become important to know what kinds of nontoxic drugs can be used together with TRAIL. We thus screened several natural compounds that can overcome resistance to TRAIL and found that a cycloanthranilylproline derivative, Fuligocandin B (FCB), an extract of myxomycete Fuligo candida, exhibited significant synergism with TRAIL. Treatment of the TRAIL-resistant cell line KOB with FCB and TRAIL resulted in apparent apoptosis, which was not induced by either agent alone. FCB increased the production of 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2), an endogenous PPARγ ligand, through activation of cyclooxygenase-2 (COX-2). This unique mechanism highlighted the fact that 15d-PGJ2 directly enhanced sensitivity to TRAIL by inhibiting multiple antiapoptotic factors. More importantly, similar effects were observed in other leukemia cell lines irrespective of their origin. The enhancement was observed regardless of PPARγ expression and was not blocked even by peroxisome proliferator-activated receptor-γ (PPARγ) siRNA. These results indicate that 15d-PGJ2 sensitizes TRAIL-resistant cells to TRAIL in a PPARγ-independent manner and that the use of 15d-PGJ2 or its inducers, such as FCB, is a new strategy for cancer therapy.