Pyranocoumarin(+/-)-4'-O-acetyl-3'-O-angeloyl-cis-khellactone induces mitochondrial-dependent apoptosis in HL-60 cells.
The pyranocoumarin (+)-4'-O-acetyl-3 'O-angeloyl-cis-khellactone (PC) isolated from Radix Peucedani (root of Peucedanum praeruptorum Dunn) showed a dose-dependent effect at 10 -30 pg/mL on causing apoptotic DNA and nuclear fragmentations in HL-60 cells. After 24 h of PC treatment there were losses of mitochondrial membrane potential and cytochrome c. PC also increased total cellular and mitochondrial Bax protein, stimulated an increase in caspase-dependent Bcl-2 cleavage but showed no effect on Bcl-Xv. These observations strongly suggest activation of the mitochondria apoptotic pathway. The pan-specific caspase inhibitor, ZVAD-fmk, abolished the PC-induced apoptosis,whereas the caspase-8 inhibitor IETD-fmk showed no effect, implying the involvement of the caspase 9 pathway. PC caused a 2 to 12 hour transient increase in phospho-ERK, and a 72 h-long activation of JNK. Pre-treatment with the MEK inhibitor PD98059, which suppresses ERK activation, paradoxically promoted PC-induced mitochondrial cytochrome c release, procaspase-3 and -8 cleavage, and enhanced apoptosis. Our results show that PC triggers mitochondria-mediated apoptosis in HL-60 cells, and the involvement of ERK and JNK signal pathways in the process.
Fong
Wang-Fun
WF
Bioactive Products Research Group, Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong SAR, P.R. China. bhwffong@cityu.edu.hk
Zhang
Jin-Xia
JX
Wu
Jimmy Yiu-Cheong
JY
Tse
Kai-Wing
KW
Wang
Cheng
C
Cheung
Hong-Yeung
HY
Yang
Meng-Su
MS
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019661:Apiaceae; D017209:Apoptosis / Q000187:drug effects*; D003374:Coumarins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018517:Plant Roots; D039681:Pyranocoumarins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011753:Pyrones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
C469046:4'-O-acetyl-3'-O-angeloylkhellactone; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D010936:Plant Extracts; D039681:Pyranocoumarins; D011753:Pyrones