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-Delta 12, 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-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), an endogenous PPAR gamma ligand, through activation of cyclooxygenase-2 (COX-2). This unique mechanism highlighted the fact that 15d-PGJ(2) 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 PPAR gamma expression and was not blocked even by peroxisome proliferator-activated receptor-gamma (PPAR gamma) siRNA. These results indicate that 15d-PGJ(2) sensitizes TRAIL-resistant cells to TRAIL in a PPAR gamma-independent manner and that the use of 15d-PGJ(2) or its inducers, such as FCB, is a new strategy for cancer therapy.
Hasegawa
Hiroo
H
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Yamada
Yasuaki
Y
Komiyama
Kanki
K
Hayashi
Masahiko
M
Ishibashi
Masami
M
Sunazuka
Toshiaki
T
Izuhara
Takeshi
T
Sugahara
Kazuyuki
K
Tsuruda
Kazuto
K
Masuda
Masato
M
Takasu
Nobuyuki
N
Tsukasaki
Kunihiro
K
Tomonaga
Masao
M
Kamihira
Shimeru
S
D017209:Apoptosis / Q000187:drug effects*; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047495:PPAR gamma / Q000096:biosynthesis; D011392:Proline / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D047495:PPAR gamma; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C490072:cycloanthranilylproline; C523500:fuligocandin B; D011392:Proline; D051546:Cyclooxygenase 2; D015230:Prostaglandin D2