Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

Abstract

Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested damage-associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines.

In Vitro Induction of Erythrocyte Phosphatidylserine Translocation by the Natural Naphthoquinone Shikonin

“…The substance has been proposed to counteract oxidative stress [1], inflammation [1,2,3], thrombosis [1,2], infections [1,2] and cancer [2,5,6,7,8]. Moreover, Shikonin has been used to support wound healing [1,2,5].…”

“…Shikonin has antioxidant [1], anti-inflammatory [1,2,3], antithrombotic [1,2], antiviral [2,4], antimicrobial [1,2], as well as anticancer [2,5,6,7,8] potency and fosters wound healing [1,2,5]. The anticancer effect of Shikonin has been attributed at least in part to the stimulation of suicidal cell death or apoptosis [9,10,11,12,13,14,15,16,17].…”

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

“…Malignant cells are capable of thermotolerance induced by heat-shock response which is accompanied by the expression of HSPs and other post-translational adaptation processes. 109 HT was shown to cause apoptosis mainly at lower temperatures (41)(42)(43) C) (and predominantly necrosis at higher temperatures (>43 C). 110 Increased immunogenicity of mouse and human tumor cells subjected to HT as well as the induction of tumor-antigen specific T cell responses in vitro and in vivo has been well documented.…”

“…109 Clinical HT was shown to affect innate and adaptive immunity; stimulating antigen presentation, maturation and migration of DCs, as well as homing of T lymphocytes to lymph nodes thereby facilitating T cell priming. The efficiency of heat-induced killing of tumor cells depends mainly on the applied temperature (ranging in most studies from 41 C to 44 C), the duration of heat treatment, tumor cell type and the cell cycle phase. Malignant cells are capable of thermotolerance induced by heat-shock response which is accompanied by the expression of HSPs and other post-translational adaptation processes.…”

Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1

“…Such a DC-based therapeutic approach has been approved by the FDA for the treatment of specific prostate cancers [12]. We and others previously reported that shikonin (SK), a phytochemical derived from the medicinal plant Lithospermum erythrorhizon (LE), can serve as an efficacious adjuvant for expression of damage-associated molecular patterns (DAMPs) and the subsequent induction of ICD in treated carcinoma cells [3, 8]. Moreover, this SK-treated tumor cell lysate (SK-TCL) can be further employed to induce strong in vivo anti-tumor activity for a dendritic cell (DC)-based cancer vaccine [8, 11].…”