Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action.
BACKGROUND
Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development.


METHODS
UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle.


RESULTS
Magnolol pretreated groups (30, 60 μ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice.Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells.


CONCLUSIONS
Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.
Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA.
Chandeshwari
C
Chilampalli
Ruth
R
Guillermo
Xiaoying
X
Zhang
Radhey S
RS
Kaushik
Alan
A
Young
David
D
Zeman
Michael B
MB
Hildreth
Hesham
H
Fahmy
Chandradhar
C
Dwivedi
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D014466:Ultraviolet Rays
D016588:Anticarcinogenic Agents; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D017705:Lignans; D050796:STAT3 Transcription Factor; C005498:magnolol; D018844:Cyclin-Dependent Kinases; D020169:Caspases