Cryptotanshinone has curative dual anti-proliferative and immunotherapeutic effects on Lewis lung carcinoma

Abstract

Abstract Lung cancer is the leading cause of cancer-related mortality, with very limited effective therapeutics. Screening of a variety of Traditional Chinese Medicines (TCMs) for capacity to inhibit the proliferation of human lung cancer A549 cells and to induce the maturation of human dendritic cells (DCs) led to the identification of cryptotanshione (CT), a compound purified from the TCM Salvia miltiorrhiza Bunge. CT can be chemically synthesized. Here CT was shown to inhibit the proliferation of mouse Lewis lung carcinoma (LLC) cells by upregulating p53 and downregulating cyclin B1 and Cdc2 and consequently inducing G2/M cell-cycle arrest of LLC cells. In addition, CT promoted phenotypic maturation of mouse and human DCs with upregulation of costimulatory and MHC molecules, and stimulated DC to produce TNFa, IL-1b and IL-12p70, but not IL-10. CT-induced maturation of DCs depended on MyD88 and also involved the activation of NF-kB, p38, and JNK. CT was effective in the treatment of established LLC tumors and, when used in combination with low-dose anti-PD-L1, can cure LLC-bearing mice with the induction of subsequent anti-LLC specific immunity. Our data indicate that CT has novel unique antitumor and immunotherapeutic activities that may provide a new promising therapeutic for the treatment of human lung cancers.