During the existing research, we comparatively inves tigated the anticancer mechanism of tanshinone IIA and cryptotanshinone from S. miltiorrhiza in CML, a type of leukemia characterized from the improved and unregulated development of predominantly myeloid cells within the bone marrow. OurgrouprecentlyreportedthattanshinoneIIAinduces apoptosis through activation of c jun N terminal kinase in KBM 5 cells. Ge et al. reported that cryptotanshinone mediatescellcyclearrestandapoptosisofmultidrug resistant K562/ADM cells by inactivating eukaryotic initiation component 4E. Additionally,we also reportedthat cryptotanshinone enhances TNF induced apoptosis in KBM 5 cells. Nonetheless,themolecularmechanismsleadingtoanti CML properties of tanshinone IIA and cryptotanshinone usually are not completely understood but. STAT is probably the important transcriptional component fami lies and plays critical roles as being a molecular target for cancer preventionand therapy.
STAT household consists of 7 vary ent subfamilies STAT1, two, 3, four, 5a, 5b, and 6, and STAT3 and 5 are constitutively activated in selleckchem cancer cells. STAT three and five are activated by nonreceptor tyrosine kinases within the Janus loved ones and c Src, and protein tyrosine phosphatases such as Src homology 2 domain containing phosphatases, phosphatase and tensin homolog, and suppressor of cytokine signaling proteins are also linked to STAT signaling. As a result, the JAK/STAT3 or five signaling continues to be believed as being a precious molecular target for cancer treatment. In our study, we located that the two tanshinone IIA and cryptotanshinone diminished the phosphorylation of JAK2, an upstream kinase of STATs, in K562 CML cells. Yet, the results of tanshinone IIA and cryptotanshinone on STAT activation were obviously different in K562 cells.
Tanshinone IIA diminished the phosphorylation of STAT5, but not STAT3, and continually prevented the STAT5/DNA binding inside the cells. In contrast, cryptotanshinone inactivated STAT3, but not STAT5, at posttranslational BIBW2992 Afatinib and transcriptional levels. On top of that, tanshinone IIA induced the expression of SHP one and two whereas cryptotanshinoneincreased the expression of SHP one, but not SHP 2, in K562 cells. The JAK/STAT signaling is involved in oncogenesis and cancer progression as a result of upregulation of antiapoptotic genes. TanshinoneIIA and cryptotanshinonecommonly repressed the expression of bcl xL, survivin and cyclin D1 in K562 cells. In contrast, only tanshinone IIA, but not cryptotanshinone, decreased the mcl 1L expression.
Apop tosis induction by tanshinone IIA or cryptotanshinone was confirmedbyactivationofcaspase 9and three,cellcycleanalysis and nuclear staining implementing PI. While tanshi none IIA and cryptotanshinone exerted anti CML routines in the distinct way by targeting the distinct STAT signaling, therewasnosignificantdifferenceintheinductionofapopto sisbythem.