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

Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salviamiotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibittumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Usinga mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo withpolarization 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 abrogatedby 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 tumorgrowth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggestedthat 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 STAT4phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, anddemonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.