Τίτλος:
A novel 7-bromoindirubin with potent anticancer activity suppresses survival of human melanoma cells associated with inhibition of STAT3 and Akt signaling
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
STAT3 and Akt signaling have been validated as potential molecular targets for treatment of cancers including melanoma. These small molecule inhibitors of STAT3 or Akt signaling are promising for developing anti-melanoma therapeutic agents. MLS-2438, a novel 7-bromoindirubin, a derivative of the natural product indirubin, was synthesized with a bromo-group at the 7-position on one indole ring and a hydrophilic group at the 3'-position on the other indole ring. We tested the anticancer activity of MLS-2438 and investigated its mechanism of action in human melanoma cell lines. Here, we show that MLS-2438 inhibits viability and induces apoptosis of human melanoma cells associated with inhibition of STAT3 and Akt signaling. Several pro-apoptotic Bcl-2 family proteins are involved in the MLS-2438 mediated apoptosis. MLS-2438 inhibits Src kinase activity in vitro and phosphorylation of JAK2, Src, STAT3 and Akt in cultured cancer cells. In contrast to the decreased phosphorylation levels of JAK2, Src, STAT3 and Akt, phosphorylation levels of the MAP K (Erk1/2) signaling protein were not reduced in cells treated with MLS-2438. These results demonstrate that MLS-2438, a novel natural product derivative, is a Src inhibitor and potentially regulates kinase activity of JAK2 and Akt in cancer cells. Importantly, MLS-2438 suppressed tumor growth with low toxicity in a mouse xenograft model of human melanoma. Our findings support further development of MLS-2438 as a potential small-molecule therapeutic agent that targets both STAT3 and Akt signaling in human melanoma cells. © 2012 Landes Bioscience.
Συγγραφείς:
Liu, L.
Kritsanida, M.
Magiatis, P.
Gaboriaud, N.
Wang, Y.
Wu, J.
Buettner, R.
Yang, F.
Nam, S.
Skaltsounis, L.
Jove, R.
Περιοδικό:
Cancer Biology and Therapy
Λέξεις-κλειδιά:
indirubin; Janus kinase 2; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mls 2438; protein kinase B; protein tyrosine kinase; STAT3 protein; unclassified drug, absence of side effects; aged; animal cell; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer cell destruction; cancer chemotherapy; cancer inhibition; cancer model; cell viability; controlled study; drug cytotoxicity; drug mechanism; drug potency; drug safety; drug targeting; enzyme inhibition; enzyme phosphorylation; female; human; human cell; IC 50; in vitro study; melanoma; melanoma cell; mouse; nonhuman; signal transduction; transcription regulation, Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Female; Humans; Indoles; Janus Kinase 2; Melanoma; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor
