A novel resveratrol derivative, HS1793, overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells.
The chemopreventive and chemotherapeutic properties associated with resveratrol offer promise for the design of new chemotherapeutic agents. However, resveratrol is not a potent cytotoxic compound when compared with other chemotherapeutic drugs. Thus, several studies were undertaken to obtain synthetic analogues of resveratrol with potent activity. The present study was undertaken to examine whether four resveratrol analogues (HS-1784, -1792, -1791 and -1793) that we had designed and synthesized show antitumor activity. Here, we observed that all of these resveratrol analogues displayed stronger antitumor effects than resveratrol in most cancer cells tested. We further examined whether HS-1793, showing potent antitumor effects in most cancer cells tested, overcomes the resistance conferred by Bcl-2, since overcoming the resistance conferred by Bcl-2 represents an attractive therapeutic strategy against cancer. Our viability assay showed that HS-1793 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Various apoptosis assessment assays demonstrated that HS-1793 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells by inducing apoptosis. Noticeably, we elucidated the marked downregulation of 14-3-3 protein by HS-1793, indicating that HS-1793 overcomes the resistance conferred by Bcl-2 in U937 cells via 14-3-3. We also observed that HS-1793 exerts its antitumor activity via Bad. However, overall data obtained from methylation specific PCR, RT-PCR and real-time PCR suggest that HS-1793 plays a role in the downregulation of 14-3-3 at a post-transcriptional level. Further understanding exactly how HS-1793 overcomes the resistance conferred by Bcl-2 via 14-3-3 may guide the development of future anticancer agents.
Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Medical Science Research Center, 3-1 Dongdaesin-dong, Seo-gu, Busan 602-714, South Korea.
Seung Hun
SH
Jeong
Wol Soon
WS
Jo
Suhee
S
Song
Hongsuk
H
Suh
So-Young
SY
Seol
Sun-Hee
SH
Leem
Taeg Kyu
TK
Kwon
Young Hyun
YH
Yoo
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008745:Methylation; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D012118:Resorcinols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
C523393:4-(6-hydroxy-2-naphthyl)-1,3-benzenediol; D000970:Antineoplastic Agents; D009284:Naphthols; D019253:Proto-Oncogene Proteins c-bcl-2; D012118:Resorcinols; D013267:Stilbenes; D000077185:Resveratrol