Abstract
Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity was evaluated in vitro (on RAW 264.7 cells and mice erythrocytes) and in vivo (acute toxicity in mice). The Ehrlich ascites carcinoma model was used to evaluate the antitumor activity of HE-02 (6.25, 12.5 or 25 mg/kg, intraperitoneally, i.p.), as well as toxicity. HE-02 induced only 5.01% of hemolysis, and reduced the viability of RAW 264.7 cells by 49.75% at 1000 µg/mL. LD50 (lethal dose 50%) was estimated at around 2000 mg/kg (i.p.). HE-02 reduced Ehrlich tumor cell viability and peritumoral microvessels density. There was an increase of Th1 helper T lymphocytes cytokine profile levels (IL-1β, TNF-α, IL-12) and a decrease of Th2 cytokine profile (IL-4, IL-10). Moreover, an increase was observed on reactive oxygen species and nitric oxide production. Weak in vivo toxicological effects were recorded. Our data provide evidence that the piperine analogue HE-02 present low toxicity, and its antitumor effect involves modulation of immune system to a cytotoxic Th1 profile.
Highlights
Cancer is a generic term that refers to a set of diseases characterized by the presence of cells in continuous proliferation with invasion and metastasis properties [1]
We investigated the toxicological and antitumor effects of a novel piperine analogue, N-(p-nitrophenyl)acetamide piperinoate (HE-02), on the Ehrlich ascites carcinoma model and its mechanism of antitumor action, by evaluating angiogenesis and the tumor microenvironment
The synthesis of the compound N-(p-nitrophenyl)acetamide piperinoate (HE-02) was carried out according to procedures described in the literature [23,24] and the synthetic steps are outlined in Scheme 1
Summary
Cancer is a generic term that refers to a set of diseases characterized by the presence of cells in continuous proliferation with invasion and metastasis properties [1]. It is one of the most common causes of high morbidity and mortality [2] which is an important public health problem worldwide [3]. M2 macrophages and Th2 lymphocytes together lead to immunosuppression, angiogenesis and tissue remodeling associated with the release of a set of cytokines, such as IL-4 and IL-10 [12] These collaborative interactions between neoplastic cells and their stroma aggregate into ectopic structures, which are chronically proliferative and often disseminative [8]. We investigated the toxicological and antitumor effects of a novel piperine analogue, N-(p-nitrophenyl)acetamide piperinoate (HE-02), on the Ehrlich ascites carcinoma model and its mechanism of antitumor action, by evaluating angiogenesis and the tumor microenvironment
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