NATURAL PRODUCTS WITH ANTICANCER ACTIVITY: A REVIEW OF IN VITRO, IN VIVO AND MOLECULAR DOCKING ASSAYS PRODUTOS NATURAIS COM ATIVIDADE ANTICÂNCER: UMA REVISÃO SOBRE ENSAIOS IN VITRO, IN VIVO E DOCKING MOLECULAR PRODUCTOS NATURALES CON ACTIVIDAD ANTICANCERÍGENA: UNA REVISIÓN DE LOS ENSAYOS IN VITRO, IN VIVO Y DE ACOPLAMIENTO MOLECULAR

Daniel Lopes Araújo1, Emanuel Osvaldo de Sousa2, Lucas Clementino da Silva Sousa3, Beatriz Gomes Sousa4, Diego Bruno Brito Cerqueira5, Eduardo Fellipe Capini de Almeida Tavares6, José Leandro da Silva Menezes Diniz7, Karol Arias Fernandes8, Ingrid Mikaela Moreira de Oliveira9, Gabriela Lais da Silva10, Mateus de Melo Terra11, Elisa Morais Barcelo12, Ludmilla Rafaela Marinho da Silva13, Maria Isabelly Leite Figueiredo14, Tiago Tavares Gonçalves15


INTRODUCTION
The evolution of man's knowledge about therapeutics of natural origin is gradual and parallel to the evolution of human history. Countless are the examples of species used in traditional practice that provide pharmacology with the active principles in use, a science known as ethnopharmacology.
The World Health Organization itself recognizes the importance of the practice and encourages all nations to preserve and promote the rational employment of knowledge derived from folk medicine (COSTA, 2018;MUNARI et al., 2021).
Plants produce a wide variety of metabolites that are gaining importance due to their therapeutic and biotechnological applications. The production levels of these metabolites are induced by environmental and genetic factors. The ability to synthesize toxic compounds is related to defense from pathogens (bacteria or fungi), herbivores such as animals or insects or suppress the growth of competitive neighboring species (NEWMAN, 2020;VOUNG, 2021;KIM et al., 2021).
Such metabolites have great potential as active ingredients, can be used directly in therapy, as precursors in chemo pharmaceutical semi-synthesis or in models for the synthesis of new principles for therapeutic use (COLONE, 2020).
Nowadays, several compounds of natural origin are used in research and for the therapy of several diseases. These products are considered privileged structures for acting on several targets, having several pharmacological activities already elucidated, such as antibacterial activity Researchers around the world have focused on research for the elucidation of the dynamics of natural products against cancer. Considered a major problem in the world, cancer is responsible for thousands of deaths worldwide. Natural compounds have not been used as strategies for new drugs for this disease considered complex, because they have some positive factors for their use, such as: easy handling and obtaining, low cost of acquisition and with fewer adverse effects and toxicity rates (RAYAN, 2017;NGUYEN et al., 2020;ESPINOSA-RODRIGUEZ et al., 2021).
In these review studies we addressed the use of natural products and their derivatives for investigation of antitumor activity. These studies were all results of in vitro, in vivo and in silico assays.
We aimed to investigate in the current literature evidence that these compounds actually have activity against cancer.

METHODOLOGY
This is an integrative literature review (IRL) with descriptive allowance. In this sense, in the first moment it elaborated the following guiding question: what are the findings in the literature that can elucidate the antitumor mechanism coming from natural products and their derivatives?
The theoretical basis was based on electronic databases: International Literature in Health Sciences (MEDLINE) through the Regional Portal of the Virtual Health Library (VHL) and in virtual libraries: Scientific Eletronic Library Online (SciELO), ScienceDirect, and Google Academico.
The terms used were identified in Medical Subjects Headings (MeHS) and/or Health Science Descriptors (DeCS). Terms such as: natural products, anticancer activity, in vivo evaluation, were used as keywords to guide the search strategy, given the specificity of the theme. The search strategies are presented in table 1.

MEDLINE
"Natural products AND Anticancer activity OR in vivo evaluation", ''Natural products AND Anticancer activity'', ''Natural products OR in vivo evaluation''.
Natural products AND Anticancer activity OR in vivo evaluation", ''Natural products AND Anticancer activity'', ''Natural products OR in vivo evaluation'' Inclusion criteria were primary articles that presented the use of natural products for antitumor activity, such as: theses, dissertations, clinical and randomized trials that had been published in English, Portuguese and available in full between the years 2015 and 2021 (last 6 years), due to being the years in which most of the publications disassembled on the topic of interest.
The exclusion criteria were editorials, review articles, those already selected in the search in another database, and those that did not answer the research question.
The search was conducted simultaneously by two independent researchers, who standardized the sequence of use of descriptors and cross-references in each database and then compared the results obtained. The articles in the sample were selected using the sequence: reading the title, reading the abstract, and reading the full text.
A total of 119 articles were found from the search of the descriptors and MeHS. Of this total, 18 were found in MEDLINE, 53 in SciELO, 28 in ScienceDirect, and 20 in Google Scholar. According to the eligibility criteria, 31 articles were selected for this review, as shown in Figure 1.  In the study by Zhang et al., (2017), their aim was to evaluate the antitumor activity of some natural products from the genus Euphorbia. In the study, they used the compound lathyrol-3-phenylacetate-5,15-diacetate (deoxy Euphorbia factor L1, DEFL1). DEFL1 showed potent inhibition against lung cancer A549 cells, with an IC50 value of 17.51 ± 0.85 μM. Furthermore, DEFL1 suppressed the healing of A549 cells in a concentration-dependent manner. Mechanistically, DEFL1 induced apoptosis, with involvement of increased reactive oxygen species (ROS), decreased mitochondrial membrane potential (ΔΨm), cytochrome c release, increased caspase-9 and 3 activity.  Malyarenko (2020) investigated the anticancer and radio sensitizing effects of the high molecular weight chloretols CcPh (Mw = 2520 Da) isolated from the brown algae of Costaria costata.

CcPh at non-toxic concentrations inhibited colony formation in colon cancer cells and significantly
increased their sensitivity to low non-toxic X-ray irradiation. The combinatorial effect of radiation and CcPh was synergistic (Combination index < 0.7). Algae chloretols may be potential candidates as radiosensitizers to improve the radiation therapy regimen.
8    Ki and co-workers (2017) present a study to investigate the effect of TDF in vivo, where C57BL/6 mice were injected with B16 melanoma cells and orally administered TDF. TDF markedly inhibited cancer cell growth and induced cell morphological changes, cell cycle arrest and apoptosis, and enhanced the expressions of death receptors (DR)-4, 5, and 6 in the cell lines. In addition, TDF up-regulated the expressions of proteins linked to mitochondrial apoptosis and induced caspasedependent cell death. It also significantly enhanced the phosphorylation of ERK1/2 and JNK, but not p38, while inhibiting NF-κB activation in cancer cells. In our mouse model, TDF significantly suppressed B16 melanoma growth to a similar extent as cisplatin (reference control) and increased immunomodulatory cytokines. In summary, this study presents the mechanism responsible for the anticancer effects of TDF in vitro and in vivo.   properties, drug availability, binding potential with selected targets, ADMET (absorption, distribution, metabolism, toxicity) were predicted. In addition, the results were compared with those of existing steroidal and nonsteroidal drugs and inhibitors of Bcl-2 and CDK-4/Cyclin D1. The results are promising and reveal that some of these steroids may be potent leads for cancer treatments.

FUTURE PROSPECTS
It is very true that studies involving the topic of cancer are of paramount importance, not only scientific importance, but also social importance (WAKS, 2019). We know that experiments seeking alternative and novel therapies for cancer are growing every day and will be so for years to come. As seen in this review study, compounds of natural origin may occupy much of the cancer research (KHAN, 2021;IQBAL et al., 2021).
In vitro and in vivo studies are quite important in this process, and one complements the other.
In silico studies, on the other hand, are also very necessary since one can get a sense of the activities of certain compounds by means of computational methods alone (SUBBURAJ et al., 2020;HUANG et al., 2020).

CONCLUDING REMARKS
Therefore, in view of the results that were explained in this review, it is noticeable that natural compounds have antitumor activity in several cancer lines. The studies and assays discussed here are important for the elucidation of the mechanism of these compounds. We hope that this review study provides, in some way, an insight to guide future research involving this theme.