Although herbal drugs are often considered safe for consumption, there is increasing evidence that some can generate undesirable health effects. However, polyphenols found in certain plants have been shown to provide a range of benefits for human health. In previous work, a standardized and quantified extract (P2Et) obtained from Caesalpinia spinosa (Dividivi) plant showed promising antioxidant, immunomodulatory, and anti-inflammatory properties in animal models of cancer and COVID-19 patients. The extract has also been subjected to genotoxicity, mutagenicity, and 28-day oral chronic toxicity evaluations, demonstrating a good safety profile. To advance preclinical and clinical development, further acute and chronic toxicity evaluations of the P2Et extract were performed. Acute toxicity tests were performed orally in Wistar rats at a dose of 2000mg/kg, indicating that the lethal dose 50 (LD₅₀) value exceeded 2000mg/kg and classifying the P2Et extract as category 5 according to the Globally Harmonized System of Classification (GHS). In this work, chronic toxicity tests were conducted for 180days on Wistar rats and New Zealand rabbits at a dose of 1000mg/kg under Good Laboratory Practice (GLP) conditions. No weight loss or alterations in biochemical and hematological parameters associated with treatment were observed in the animals, suggesting the absence of toxicity in the assessed parameters. These results indicate that the P2Et extract is safe for oral administration at doses up to 1000mg/kg body weight over a six-month period.

The need for new therapeutic approaches to improve the response in acute leukemia (AL), either by directing therapy or with new therapeutic alternatives, has been a research and clinical interest topic. We evaluated whether blasts from AL patients were sensitive ex vivo to the induction chemotherapy and whether the extracts of Petiveria alliacea (Anamu SC) and Caesalpinia spinosa (P2Et) modulated the sensitivity of leukemic cells to death. Bone marrow samples were taken from 26 patients with de novo AL and 6 in relapse, and the cytotoxicity of the extracts alone or in combination with the chemotherapeutic was evaluated by XTT. Patients were classified as good (GR) and bad responders (BR) according to the ex vivo test. 70.5% of the GR patients to the ex vivo test achieved postinduction remission to induction chemotherapy with a median overall survival of 12.50 months versus 7.23 months in the two groups. Furthermore, it was found that the ex vivo response to extracts and chemotherapeutics is heterogeneous and shows an exclusive pattern between the extracts, Anamu being the more effective in inducing cell death. The combination of extracts with chemotherapeutic agents showed synergistic or antagonistic effects in the patients’ blasts. These results show that the ex vivo evaluation of the sensitivity to induction drugs using primary blasts from patients exhibits a correlation with the response to induction chemotherapy in patients. These analyses would allow establishing a system to predict response to treatment and determine ex vivo susceptibility to new therapies under development, among which is phytotherapeutics.

The polyphenol-enriched extract called P2Et derived from Caesalpinia spinosa (C. spinosa) had antitumor and immunomodulatory activities reported in breast cancer, leukemia, and melanoma. The aim of this study was to evaluate the safety and maximum tolerated dose of P2Et extract in Colombian healthy volunteers in a phase 1 clinical trial, open labelled, single-arm, dose-escalation design 3+3. Seven healthy volunteers were included; P2Et was administrated in capsules of 600mg/d for 28 days. Analysis by intention to treat was performed. 4 volunteers showed adverse events and discontinued the intervention. 94.6 of AE were grade 1, and most of AE had a reasonable possibility of a relationship with the P2Et (83.8). We found that the oral administration of P2Et is safe in healthy humans with a maximum tolerated dose of 600mg/d. There was no severe toxicity; most of the adverse events were mild, without significant changes in the safety parameters evaluated.

The poor response, adverse effects and drug resistance to treatment of acute myeloid leukemia (AML) have led to searching for safer and more effective therapeutic alternatives. We previously demonstrated that the alcoholic extract of Petiveria alliacea (Esperanza) has a significant in vitro antitumor effect on other tumor cells and also the ability to regulate energy metabolism. We evaluated the effect of the Esperanza extract in vitro and in vivo in a murine model of AML with DA-3/ER-GM cells. First, a chemical characterization of the extract was conducted through liquid and gas chromatography coupled with mass spectrometry. In vitro findings showed that the extract modulates tumor metabolism by decreasing glucose uptake and increasing reactive oxygen species, which leads to a reduction in cell proliferation. Then, to evaluate the effect of the extract in vivo, we standardized the mouse model by injecting DA-3/ER-GM cells intravenously. The animals treated with the extract showed a lower percentage of circulating blasts, higher values of hemoglobin, hematocrit, and platelets, less infiltration of blasts in the spleen, and greater production of cytokines compared to the control group. These results suggest that the antitumor activity of this extract on DA-3/ER-GM cells can be attributed to the decrease in glycolytic metabolism, its activity as a mitocan, and the possible immunomodulatory effect by reducing tumor proliferation and metastasis.

The modulation of the tumor microenvironment by natural products may play a significant role in the response of tumor cells to chemotherapy. In this study, we evaluated the effect of extracts derived from P2Et (Caesalpinia spinosa) and Anamú-SC (Petiveria alliacea) plants, previously studied by our group, on the viability and ROS levels in the K562 cell line (Pgp− and Pgp+), endothelial cells (ECs, Eahy.926 cell line) and mesenchymal stem cells (MSC) cultured in 2D and 3D. The results show that: (a) the two botanical extracts are selective on tumor cells compared to doxorubicin (DX), (b) cytotoxicity is independent of the modulation of intracellular ROS for plant extracts, unlike DX, (c) the interaction with DX can be influenced by chemical complexity and the expression of Pgp, (d) the 3D culture shows a greater sensitivity of the tumor cells to chemotherapy, in co-treatment with the extracts. In conclusion, the effect of the extracts on the viability of leukemia cells was modified in multicellular spheroids with MSC and EC, suggesting that the in vitro evaluation of these interactions can contribute to the comprehension of the pharmacodynamics of the botanical drugs.

Background. The impact of the dose intensity administered in consolidation in Latin America is unknown. This study aimed to evaluate the relative dose intensity (RDI) in consolidation and its impact in overall survival. Methods. A retrospective study of 86 patients with AML who were diagnosed between 2010 and 2016 with a 2-year follow-up in a fourth-level Colombian hospital was carried out. Clinical characteristics were reported, Kaplan-Meier was used for estimating the overall survival, and Cox regression was used for multivariate analysis. Results. The median overall survival (OS) was 20.83 months, and the median event-free survival (EFS) was 16.83 months. 64.3% of the patients achieved remission after the 7+3 chemotherapy induction treatment. Patients under 30 years of age, with white blood cell counts less than 100.000 cells/mm3 who responded to induction treatment had a better OS. Additionally, patients receiving an RDI greater than 0.75 of the planned consolidation dose had better survival. The prognostic variables with impact in the OS were the leukocyte count in peripheral blood at diagnosis, the RDI in consolidation treatment with HIDAC and the response obtained after induction. Conclusion. This retrospective study allowed us to know the epidemiology of AML in a reference Colombian Hospital. Additionally, in our knowledge, it is the first study that reports the RDI in consolidation with HIDAC in Latin America as a prognostic factor that directly impacts the OS.