A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia
Author: Ji Hoon Jung and Miyong Yun and Eun-Jeong Choo and Sun-Hee Kim and Myoung-Seuk Jeong and Deok-Beom Jung and Hyemin Lee and Eun-Ok Kim and Nobuo Kato and Bonglee Kim and Sanjay K. Srivastava and Kunihiro Kaihatsu and Sung-Hoon Kim
EGCG is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent. In the current study, EGCG derivatives were compared and evaluated for their stability and anti-tumour activity in human CML K562 and KBM5 cells. EGCG-MP showed most prolonged stability compared to other EGCG derivatives. EGCG-MP exerted significant cytotoxicity and increased apoptosis in K562 and KBM5 cells more effectively than the other EGCG derivatives. In addition, EGCG-MP dramatically induced SHP-1 leading to the decrease of BCR-ABL and STAT3 phosphorylation in CML cells, compared to treatment with EGCG. Furthermore, EGCG-MP reduced the phosphorylation of STAT3 and survival genes in K562 cells, compared to treatment with EGCG. Conversely, depletion of SHP-1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG-MP to suppress phosphorylation of BCR-ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG-MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared to the untreated control or EGCG-treated group. Consistently, immunohistochemistry revealed increased caspase 3 and SHP-1 activity and decreased phosphorylation of BCR-ABL in the EGCG-MP-treated group in the EGCG-treated group. Our findings demonstrate that EGCG-MP induces SHP-1-mediated inhibition of BCR-ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG as a potent chemotherapeutic agent for CML treatment.
