Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Abstract

Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibit tumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Using a mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo with polarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation, and also increased IFN-γ and perforin production of CD4+ T cells in response to tumor-activated splenocytes. Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogated by concanamycin A(CMA), a perforin inhibitor, but not IFN-γ Ab. On the other hand, after depletion of CD4+ T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumor growth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggested that CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin. We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, and demonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.

Isocryptotanshinone Induced Apoptosis and Activated MAPK Signaling in Human Breast Cancer MCF-7 Cells

“…Several tanshinones isolated from S. miltiorrhiza , including tanshinone I, tanshinone IIA, CTS, and dihydrotanshinone I, inhibit the growth of various human cancer cell lines through antiproliferative (e.g., cell cycle arrest) and proapoptotic effects [ 7 10 ]. CTS inhibits proliferation and induces apoptosis in several cancer cell lines, including human liver cancer cells [ 18 ], prostate cancer cells [ 17 19 ], leukemia cells [ 20 ], glioma cells [ 21 ], breast cancer cells [ 22 ], and lung cancer cells [ 23 ]. The structure of the tanshinone ICTS is similar to that of CTS.…”

The transcriptional STAT3 is a potential target, whereas transcriptional STAT5A/5B/6 are new biomarkers for prognosis in human breast carcinoma

“…However, considering hormone receptor criterions, STAT4 showed positive correlation with TNBC, a more aggressive type with poor prognosis. Crytotanshinone (CPT) showed potential therapeutic value in animal breast model through enhancing cytotoxic CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation [30], suggesting that STAT4 may be play opposite function with STAT3 in human cancers.…”

Cryptotanshinone inhibits lung tumor growth by increasing CD4+ T cell cytotoxicity through activation of the JAK2/STAT4 pathway

“…In the present study, treatment with cryptotanshinone significantly increased the cytotoxicity of the CD4 + T cells, but did not affect the cytotoxicity of the CD8 + T cells. Zhou et al suggested that cryptotanshinone inhibited breast tumor growth by increasing the cytotoxicity of CD4 + T cells through activation of the JAK2/STAT4/perforin pathway (23).…”