Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent.
Melanoma transformation progresses in a multistep fashion from precursor lesions such as congenital naevi. Exposure to ultraviolet (UV) light promotes this process. Betulinic acid (BA) was identified by our group as a selective inhibitor of melanoma that functions by inducing apoptosis. The present study was designed to investigate the effect of BA and UV-C (254 nm) on cultured congenital melanocytic naevi (CMN) cells, using the single-cell gel electrophoresis (comet) assay to detect DNA damage. Exposure to UV light induced a 1.7-fold increase in CMN cells (P = 0.008) when compared with controls. When a p53 genetic suppressor element that encodes a dominant negative polypeptide (termed GSE56) was introduced into the CMN cells, the transfected cells were more sensitive to UV-induced DNA breakage. This suggests that p53 can protect against UV-induced DNA damage and subsequent melanoma transformation. Pretreatment with BA (3 microm) for 48 h resulted in a 25.5% reduction in UV-induced DNA breakage in the CMN cells (P = 0.023), but no changes were observed in the transfected cells. However, Western blot analysis revealed no changes in the p53 or p21 levels in BA-treated cells, suggesting that BA might mediate its action via a non-p53 pathway. These data indicate that BA may have an application as a chemopreventive agent in patients with congenital naevi.
Salti
G I
GI
Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, 60612, USA. geosalti@uic.edu
Kichina
J V
JV
Das Gupta
T K
TK
Uddin
S
S
Bratescu
L
L
Pezzuto
J M
JM
Mehta
R G
RG
Constantinou
A I
AI
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D020552:Comet Assay; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D015536:Down-Regulation; D005799:Genes, Dominant; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008544:Melanocytes / Q000473:pathology*; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy*; D009506:Nevus / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D020741:rho GTP-Binding Proteins / Q000235:genetics; D000094062:Betulinic Acid
D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D004247:DNA; D020741:rho GTP-Binding Proteins; D000094062:Betulinic Acid