Abstract
BackgroundPlatinum-based chemotherapy is emerging as the first line of treatment for castration resistant prostate cancer. Among the family of platinum (IV)-based compounds, a member known as CPA-7 inhibits the growth of multiple cancer cell lines. However, how and to what extent CPA-7 elicits its anti-prostate cancer effects in vivo is largely unknown.MethodsIn this study, we firstly assessed the potential toxicity of the synthesized CPA-7 in a prostate cancer model as well as in normal mice. Next, we evaluated the in vitro effects of CPA-7 on the growth of prostate cancer cells using cell counting assay, and calculated the tumor sizes and cumulative survival rate of the tumor bearing mice by Kaplan-Meier method during CPA-7 treatment. Then we measured the expression level of the activated form of STAT3 (one targets of CPA-7) and its transcriptive activity post CPA-7 treatment by synergistically using western blot, IHC, and firefly luciferase reporter assays. Finally, effects of CPA-7 on immune cell trafficking in the tumor draining lymph nodes and in the spleens are evaluated with flow cytometry.ResultsTreatment with CPA-7 significantly inhibited growth of prostate cancer cells in vitro, and also in mice resulting in a prolonged survival and a decreased recurrence rate. These therapeutic effects are due, at least in part, to functional depletion of STAT3 in prostate tumor tissue as well as in the surrounding areas of tumor cell invasion. CPA-7 treatment also resulted in a reduced level of regulatory T cells and increased levels of cytotoxic T and T helper cells in the spleen and in tumor infiltrating lymph nodes. This favorable effect on immune cell trafficking may account for the amnestic immune response against recurrent prostate cancer.ConclusionsCPA-7 is a promising new therapeutic agent for prostate cancer that both inhibits tumor cell proliferation and stimulates anti-tumor immunity. It has potential as first line treatment and/or as an adjuvant for refractory prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2488-6) contains supplementary material, which is available to authorized users.
Highlights
Platinum-based chemotherapy is emerging as the first line of treatment for castration resistant prostate cancer
In addition to directly function on tumor cells, Signal transducer and activator of transcription 3 (STAT3) plays pivotal roles in anti-cancer immunity, as a potent negative regulator of T helper 1 (TH1)-cell-mediated inflammation, and as an important activator of genes that are crucial for immunosuppression [11]
Synthesized CPA-7 had little impact on the body weight of the mice when applied at no more than 1.5 mg/kg Because side effects are a major concern with platinumbased antineoplastics, we evaluated the safety of CPA-7
Summary
Platinum-based chemotherapy is emerging as the first line of treatment for castration resistant prostate cancer. Among the family of platinum (IV)-based compounds, a member known as CPA-7 inhibits the growth of multiple cancer cell lines. Androgen deprivation therapy (ADT) is used as a first line therapy for hormone sensitive, metastatic prostate cancer (PC). Activation of STAT3 is found in approximate 70 % of the solid malignancies, including hematological malignancies as well as diverse solid tumors such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers [8, 9]. In addition to directly function on tumor cells, STAT3 plays pivotal roles in anti-cancer immunity, as a potent negative regulator of T helper 1 (TH1)-cell-mediated inflammation, and as an important activator of genes that are crucial for immunosuppression [11]. Targeting STAT3 could well reduce tumorigenesis and modulate tumour-induced immunosuppression
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