Anti-inflammatory and antitumor activity of active principles from Croton campestris A. St.-Hil: mechanisms of action and links

Abstract

There were 14.1 million new cancer cases, 8.2 million cancer deaths and 32.6 million people living with cancer in 2012 worldwide and the most incident types were lung (13%), breast (11.9%) and colorectal cancer (9.7%), with 19.4%, 6.4% and 8.5% of mortality respectively. In this context, natural products are an important source of new active compounds. More than 50% of the chemotherapies used are from natural source, including synthetic derivatives. One of the most diverse genre of plants is Croton, from Euphorbiaceae family with numerous species, known to have compounds which possess many biological properties. Croton campestris A.St.-Hil, popularly known as "velame-do-campo", is a native bush found mainly in Brazilian Southeast and Northeast. Our studies using in vivo models has shown the potent antitumor of fraction CFqb14 in the Ehrlich solid tumor model (paw and flank), which inhibited in 22,5% tumor growth with 4 mg/kg treatment, 3 times/week, intraperitoneal route. The same fraction presented a potent anti-inflammatory activity in acute inflammation models (carrageenan-induced paw edema and peritonitis), inhibiting the migration of leukocytes and edema formation. The results obtained until now suggest that the antitumor and anti-inflammatory activities of fraction CFqb14 may be connected. Having in mind the potent antiproliferative and anti-inflammatory activities of the fraction CFqb14 from Croton campestris, the lack of biological studies with this specie and the link between cancer and inflammation, we objectify to elucidate the interleukins, cytokines, chemokines and other molecules involved in the antiproliferative and anti-inflammatory activities of this fraction or similar, in an attempt to connect these activities. The main aim of this 6 months project is to complement the PhD project, addressing the role of inflammation in the mechanism of action the active fraction CFqb14 (and similar fraction) from C. campestris in carcinogenesis. The strategies to be used to achieve these objectives are the evaluation of the anti-inflammatory and antitumor activity of fraction CFqb14 on acute colitis, colitis-associated colorectal cancer and sporadic colorectal cancer models in mice, focusing in the inflammatory microenvironment. Moreover, as fraction CFqb14 has in vitro selectivity for human lung cancer cell line, we will evaluate its antiproliferative activity in a lung cancer cell line implanted in the subcutaneous of mice, as well as the parameters related to proliferation and cell death. The methodology will include tissue and molecular evaluations, Immunohistochemistry, ELISA, RT-qPCR analysis, Flow Cytometry etc. Moreover, the aplicant will learn new techniques and unique genetic animal models of inflammation and cancer (particularly lung and colorectal cancers) in the facilities of the specialized center of research and treatment of cancer, the Fox Chase Cancer Center - USA, with Dr. Sergei Grivennikov's group. Besides the scientific contribution regarding the investigation of the mechanisms of action of fraction CFqb14 and similar from C. campestris, the experience in Dr. Grivennikov's lab will be of great importance to complete and enrich this work, as well as to improve the molecular biology skills and experiences with new animal models. These proposed experiments will provide unprecedented data and enrich the study. The results can provide the base for future studies of compounds from this Brazilian plant, which can become candidates for clinical studies if its therapeutical potentials are positives. (AU)