title: Spirooxindole derivative SOID-8 induces apoptosis associated with inhibition of JAK2/STAT3 signaling in melanoma cells.
abstract: Melanoma is generally refractory to current chemotherapy, thus new treatment strategies are needed. In this study, we synthesized a series of spirooxindole derivatives (SOID-1 to SOID-12) and evaluated their antitumor effects on melanoma. Among the 12 spirooxindole derivatives, SOID-8 showed the strongest antitumor activity by viability screening. SOID-8 inhibited viability of A2058, A375, SK-MEL-5 and SK-MEL-28 human melanoma cells in a dose- and time-dependent manner. SOID-8 also induced apoptosis of these tumor cells, which was confirmed by positive Annexin V staining and an increase of poly(ADP-ribose) polymerase cleavage. The antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was downregulated and correlated with SOID-8 induced apoptosis. In addition, SOID-8 reduced tyrosine phosphorylation of Signal Tansducer and Activator of Transcription 3 (STAT3) in both dose- and time-dependent manners. This inhibition was associated with decreased levels of phosphorylation of Janus-activated kinase-2 (JAK2), an upstream kinase that mediates STAT3 phosphorylation at Tyr705. Accordingly, SOID-8 inhibited IL-6-induced activation of STAT3 and JAK2 in melanoma cells. Finally, SOID-8 suppressed melanoma tumor growth in a mouse xenograft model, accompanied with a decrease of phosphorylation of JAK2 and STAT3. Our results indicate that the antitumor activity of SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells. These findings suggest that the spirooxindole derivative SOID-8 is a promising lead compound for further development of new preventive and therapeutic agents for melanoma.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tian
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.forename: Lucy
authors.initials: L
authors.lastname: Liu
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yakushijin
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yakushijin
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D000818:Animals; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D053614:Janus Kinase 2 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000078183:Oxindoles; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D017304:Annexin A5; D007211:Indoles; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000078183:Oxindoles; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013141:Spiro Compounds; C022960:2-oxindole; D011065:Poly(ADP-ribose) Polymerases; C507924:JAK2 protein, human; D053614:Janus Kinase 2