A derivative of epigallocatechin‐3‐gallate induces apoptosis via SHP‐1‐mediated suppression of BCR‐ABL and STAT3 signalling in chronic myelogenous leukaemia

Abstract

Background and PurposeEpigallocatechin‐3‐gallate (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.Experimental ApproachDerivatives of EGCG were evaluated for their stability and anti‐tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells.Key ResultsEGCG‐mono‐palmitate (EGCG‐MP) showed most prolonged stability compared with other EGCG derivatives. EGCG‐MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG‐MP induced Src‐homology 2 domain‐containing tyrosine phosphatase 1 (SHP‐1) leading decreased oncogenic protein BCR‐ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG‐MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared 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 with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP‐1 activity and decreased phosphorylation of BCR‐ABL in the EGCG‐MP‐treated group relative to that in the EGCG‐treated group.Conclusions and ImplicationsEGCG‐MP induced SHP‐1‐mediated inhibition of BCR‐ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment.

(−)‐Epigallocatechin‐3‐gallate induces cell apoptosis in chronic myeloid leukaemia by regulating Bcr/Abl‐mediated p38‐MAPK/JNK and JAK2/STAT3/AKT signalling pathways

“…JAKs lead to the recruitment and activation of STAT3, and activated STAT3 promotes tumourigenesis by blocking apoptosis and enhancing proliferation. Jung et al reported that EGCG‐MP suppressed the phosphorylation of STAT3 in a concentration‐dependent manner in K562 cells. AKT activation has also been identified as a key signalling molecule in Bcr/Abl‐mediated leukaemogenesis .…”

Leukemia therapy by flavonoids: Future and involved mechanisms

“…Moreover, icariside II obstructed the phosphorylation of Src, representing that it suppressed STAT3 signaling pathway via inhibition of JAK2 and Src in U937 cells (Kang et al, ). Similarly, CML cells apoptosis rate increased after these cells treatment with flavonoids via the inhibition of STAT3 signaling pathway (J. H. Jung et al, ). More research have demonstrated that flavonoid EGCG‐MP blocked the phosphorylation of STAT3 and subsequently induced the expression of Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1) in K562 cells, suggesting that the cytotoxic and apoptotic functions of EGCG‐MP occurred by suppression of STAT3 (J. H. Jung et al, ).…”

Ethyl acetate extract from Selaginella doederleinii Hieron inhibits the growth of human lung cancer cells A549 via caspase-dependent apoptosis pathway

“…The effect of ethyl acetate extract on cell growth was evaluated by previous method with a little modification (Jung et al, 2015;Mei et al, 2015). In brief, 3×10 3 cells were seeded in 96-well plates and permitted to incubate overnight.…”