Perilla leaf, Perilla frutescens, induces apoptosis and G1 phase arrest in human leukemia HL-60 cells through the combinations of death receptor-mediated, mitochondrial, and endoplasmic reticulum stress-induced pathways.
Since it has been reported that Perilla leaves (Perilla frutescens) have antimutagenic, antioxidant, and anti-inflammatory properties, we hypothesized that Perilla leaves may have a potential anticancer activity. Therefore, we examined the possibility that cancer cell growth is reduced by treatment with a Perilla leaf ethanol extract (PLE) using human leukemia HL-60 cells and then investigated the mechanism of the growth inhibition. We found that PLE treatment suppressed cell viability in a dose-dependent manner. Flow cytometric analysis revealed that PLE treatment caused the appearance of a sub-G1 DNA peak and induced cell cycle arrest at the G1 phase. We detected DNA ladders in PLE-treated cells by agarose gel electrophoresis, and the cleavage of pro-caspase-3 and poly(ADP-ribose) polymerase with remarkable activation of caspase-8, -9, and -3. Western blot analysis revealed dose-dependent increases in Bax and cytochrome c in cytosol fractions and decreased Bid and pro-caspase-8 and -3 in PLE-treated cells. In addition, glucose-regulated protein 78, phosphorylated eukaryotic translation initiation factor 2 subunit alpha, phosphorylated c-jun N-terminal kinase, and p21 levels were increased by PLE treatment in a dose-dependent manner, whereas the p27 level was not changed. We concluded that PLE induced apoptosis through the combinations of mitochondrial, death receptor-mediated, and endoplasmic reticulum pathways and suppressed the cell proliferation via p21-mediated G1 phase arrest in HL-60 cells.
Kwak
Chung Shil
CS
Institute on Aging, Seoul National University, Seoul. kwakcs@snu.ac.kr
Yeo
Eui Ju
EJ
Moon
Sung Chae
SC
Kim
Young Wha
YW
Ahn
Hong Ju
HJ
Park
Sang Chul
SC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D016193:G1 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D031344:Perilla frutescens / Q000737:chemistry*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D018515:Plant Leaves; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D053418:Death Domain Receptor Signaling Adaptor Proteins; D005419:Flavonoids; D010936:Plant Extracts; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases