Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells

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Jung JH, Kwon T-R, Jeong S-J, et al. Evidence-Based Complementary and Alternative Medicine. Volume 2013 (2013) http://dx.doi.org/10.1155/2013/805639
Abstract
Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear.
In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3.
In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells.
Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells.
Introduction
Salvia miltiorrhiza Bunge (Danshen) is a traditional medicinal herb widely used for treating cardiovascular disease in Korea, China, and Japan [1]. To date, over 90 kinds of chemical constituents from S. miltiorrhiza have been reported [2, 3]. Of the phytochemicals, tanshinones are a group of lipophilic abietane diterpene compounds including tanshinone I, tanshinone IIA-B, cryptotanshinone, dihydrotanshinone I, isotanshinone I, and isocryptotanshinone I-II and have been extensively investigated [1, 4–7].
In particular, tanshinone IIA and cryptotanshinone have been presented the potential as anticancer drugs by targeting the multiple signaling pathways [8–18].STAT family is transcriptional factors that play key roles in cytokine signaling [19]. STAT proteins are constitutively activated in cancer cells or tissues and thus have been suggested as attractive molecular target(s) for cancer therapy. In light of these events, numerous groups reported the inhibitory effects of plant polyphenols such as curcumin, resveratrol, piceatannol, and EGCG on STAT activation in various cancer cells [19, 20].
Tanshinone IIA and cryptotanshinone were also shown to have the inhibitory effects on the STAT activation in C6 glioma [21] and DU145 prostate cancer cells [22], respectively. However, there is no report on the molecular mechanisms leading to anticancer activity of tanshinone IIA and cryptotanshinone through the STAT signaling pathway in leukemia cells.
Conclussion
Our findings clearly demonstrate that anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct JAK/STAT3/5 and SHP1/2 signaling in K562 cells. Of note, tanshinone IIA showed more potential for the synergy with imatinib compared with cryptotanshinone as a potent candidate for combination therapy.

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