ABSTRACT
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 2000 mg/kg, indicating that the lethal dose 50% (LD50) value exceeded 2000 mg/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 180 days on Wistar rats and New Zealand rabbits at a dose of 1000 mg/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 1000 mg/kg body weight over a six-month period.
ABSTRACT
The Covid-19 infection outbreak led to a global epidemic, and although several vaccines have been developed, the appearance of mutations has allowed the virus to evade the immune response. Added to this is the existing risk of the appearance of new emerging viruses. Therefore, it is necessary to explore novel antiviral therapies. Here, we investigate the potential in vitro of plant extracts to modulate cellular stress and inhibit murine hepatitis virus (MHV)-A59 replication. L929 cells were treated with P2Et (Caesalpinia spinosa) and Anamu SC (Petiveria alliacea) plant extracts during infection and virus production, ROS (reactive oxygen species), UPR (unfolded protein response), and autophagy were assessed. P2Et inhibited virus replication and attenuated both ROS production and UPR activation induced during infection. In contrast, the sustained presence of Anamu SC during viral adsorption and replication was required to inhibit viral infection, tending to induce pro-oxidant effects, and increasing UPR gene expression. Notably, the loss of the PERK protein resulted in a slight decrease in virus yield, suggesting a potential involvement of this UPR pathway during replication. Intriguingly, both extracts either maintained or increased the calreticulin surface exposure induced during infection. In conclusion, our findings highlight the development of antiviral natural plant extracts that differentially modulate cellular stress.
ABSTRACT
Natural products obtained from Petiveria alliacea (Anamu-SC) and Caesalpinia spinosa (P2Et) have been used for cancer treatment, but the mechanisms by which they exert their antitumor activity appear to be different. In the present work, we show that the Anamu-SC extract reduces tumor growth in the 4T1 murine mammary carcinoma model but not in the B16-F10 melanoma model, unlike the standardized P2Et extract. Both extracts decreased the levels of interleukin-10 (IL-10) in the B16-F10 model, but only P2Et increased the levels of tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). Likewise, co-treatment of P2Et and doxorubicin (Dox) significantly reduced tumor size by 70% compared to the control group, but co-treatment of Anamu-SC with Dox had no additive effect. Analysis of intratumoral immune infiltrates showed that Anamu-SC decreased CD4+ T cell frequency more than P2Et but increased CD8+ T cell frequency more significantly. Both extracts reduced intratumoral monocytic myeloid-derived suppressor-like cell (M-MDSC-LC) migration, but the effect was lost when co-treated with doxorubicin. The use of P2Et alone or in co-treatment with Anamu-SC reduced the frequency of regulatory T cells and increased the CD8+/Treg ratio. In addition, Anamu-SC reduced glucose consumption in tumor cells, but this apparently has no effect on IFNγ- and TNFα-producing T cells, although it did reduce the frequency of IL-2-producing T cells. The efficacy of these herbal preparations is increasingly clear, as is the specificity conditioned by tumor heterogeneity as well as the different chemical complexity of each preparation. Although these results contribute to the understanding of specificity and its future benefits, they also underline the fact that the development of each of these standardized extracts called polymolecular drugs must follow a rigorous path to elucidate their biological activity.
Subject(s)
Biological Products , Carcinoma , Melanoma, Experimental , Mice , Animals , Biological Products/therapeutic use , Disease Models, Animal , Tumor Necrosis Factor-alpha/therapeutic use , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Melanoma, Experimental/pathology , Interferon-gamma/therapeutic use , Immunity , Mice, Inbred C57BLABSTRACT
Previously, studies have shown that leukemic cells exhibit elevated glycolytic metabolism and oxidative phosphorylation in comparison to hematopoietic stem cells. These metabolic processes play a crucial role in the growth and survival of leukemic cells. Due to the metabolic plasticity of tumor cells, the use of natural products has been proposed as a therapeutic alternative due to their ability to attack several targets in tumor cells, including those that could modulate metabolism. In this study, the potential of Petiveria alliacea to modulate the metabolism of K562 cell lysates was evaluated by non-targeted metabolomics. Initially, in vitro findings showed that P. alliacea reduces K562 cell proliferation; subsequently, alterations were observed in the endometabolome of cell lysates treated with the extract, mainly in glycolytic, phosphorylative, lipid, and amino acid metabolism. Finally, in vitro assays were performed, confirming that P. Alliacea extract decreased the oxygen consumption rate and intracellular ATP. These results suggest that the anti-tumor activity of the aqueous extract on the K562 cell line is attributed to the decrease in metabolites related to cell proliferation and/or growth, such as nucleotides and nucleosides, leading to cell cycle arrest. Our results provide a preliminary part of the mechanism for the anti-tumor and antiproliferative effects of P. alliacea on cancer.
Subject(s)
Leukemia, Myeloid , Phytolaccaceae , Humans , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , K562 Cells , Leukemia, Myeloid/drug therapy , Phytolaccaceae/chemistryABSTRACT
Acute leukemias (AL) are aggressive neoplasms with high mortality rates. Metabolomics and oxidative status have emerged as important tools to identify new biomarkers with clinical utility. To identify the metabolic differences between healthy individuals (HI) and patients with AL, a multiplatform untargeted metabolomic and lipidomic approach was conducted using liquid and gas chromatography coupled with quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS or GC-QTOF-MS). Additionally, the total antioxidant capacity (TAC) was measured. A total of 20 peripheral blood plasma samples were obtained from patients with AL and 18 samples from HI. Our analysis revealed 135 differentially altered metabolites in the patients belonging to 12 chemical classes; likewise, the metabolic pathways of glycerolipids and sphingolipids were the most affected in the patients. A decrease in the TAC of the patients with respect to the HI was evident. This study conducted with a cohort of Colombian patients is consistent with observations from other research studies that suggest dysregulation of lipid compounds. Furthermore, metabolic differences between patients and HI appear to be independent of lifestyle, race, or geographic location, providing valuable information for future advancements in understanding the disease and developing more global therapies.
ABSTRACT
BACKGROUND: Chemotherapy in breast cancer is effective but can generate significant toxicity and lead to tumor resistance. Joint treatment with standardized plant extracts can be an alternative to improve the response and allow an effective activation of the antitumor immune response that favors recovery in the short and long term. The P2Et extract of Caesalpinia spinosa presents antitumor activity in cells and animal models of breast cancer, improves the tumor microenvironment, and induces activation of the specific immune response against the tumor and is synergistic when used together with anthracyclines, which makes it a good candidate for evaluation in patients. METHODS: Conducted at a single center, this phase II study is a randomized, double-blind, placebo-controlled trial aimed at assessing the safety and efficacy of P2Et extract in patients diagnosed with stage II and III breast cancer, who are eligible for neoadjuvant treatment. The study aims to determine the safety profile at the previously established optimal biological dose from phase I trial while investigating various efficacy outcomes. These outcomes include improvements in quality of life, immunomodulation, metabolic profile, microbiome, as well as clinical indicators such as tumor reduction, disease-free survival, and pathological response, assessed at different stages of the treatment regimen. DISCUSSION: Treatment with the P2Et extract in breast cancer patients is hypothesized to enhance overall well-being, positively influencing their quality of life, while also triggering an antitumor immune response and enhancing immune infiltration. These combined effects have the potential to contribute to improved long-term survival outcomes for patients receiving the phytomedicine alongside neoadjuvant chemotherapy treatment. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT05007444. First Registered August 16th, 2021. Last Updated: August 9th, 2022.
Subject(s)
Caesalpinia , Neoplasms , United States , Animals , Quality of Life , Cyclic S-Oxides , Morpholines , Randomized Controlled Trials as Topic , Clinical Trials, Phase II as Topic , Clinical Trials, Veterinary as TopicABSTRACT
BACKGROUND: The energy metabolism of drug-resistant tumor cells can provide a survival advantage during therapy, and treatment itself may influence metabolic reprogramming. Petiveria alliacea (Traditional name: Anamu) could inhibit glycolysis and OXPHOX modulating tumor metabolism, making it a potential treatment for tumors with altered metabolism. This clinical study aims to evaluate the safety and efficacy of a standardized Anamu phytomedicine called Esperanza in treating gastric tumors and acute leukemias. METHODS: This is a prospective, open label, phase I/ randomized, double-blind single-center phase II study designed to evaluate the safety and efficacy of Esperanza extract in patients with metastatic gastrointestinal tumors and acute leukemias. In stage 1, the study will determine the MTD and assess safety. In stage 2, safety at the MTD will be evaluated, and the efficacy of Esperanza extract will be explored in both metastatic gastric tumors and acute leukemias. Quality of life improvement will be the primary outcome in the gastric tumor group, while different efficacy outcomes will be assessed in the acute leukemia group. A placebo group will be used for comparison in the gastric tumor group, and a historical control group will be used in the acute leukemia arm. DISCUSSION: This clinical trial aims to evaluate the safety profile of the Esperanza extract in patients with metastatic gastrointestinal tumors and acute leukemias, while exploring its potential efficacy in conjunction with standard treatment for these pathologies. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT05587088. Registered October 19th, 2022.
Subject(s)
Leukemia , Phytolaccaceae , Stomach Neoplasms , United States , Humans , Stomach Neoplasms/drug therapy , Prospective Studies , Quality of Life , Leukemia/drug therapy , Randomized Controlled Trials as Topic , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as TopicABSTRACT
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.
Subject(s)
Leukemia, Myeloid , Phytolaccaceae , Animals , Mice , Tumor Burden , Gas Chromatography-Mass Spectrometry , Plant Extracts/pharmacology , Plant Extracts/therapeutic useABSTRACT
Although the antitumor effect of P. nigrum has been widely studied, research related to its possible immunomodulatory effects is relatively scarce. Here, the antitumor and immunomodulatory activity of an ethanolic extract of P. nigrum were evaluated in the murine models of 4T1 breast cancer and B16-F10 melanoma. In vitro evaluations showed that the P. nigrum extract has cytotoxic activity, induces apoptotic cell death, and has a pro-oxidant effect in both cell lines, but it regulates glucose uptake differently in both lines, decreasing it in 4T1 but not in B16-F10. P. nigrum extract significantly reduced tumor size in both models and decreased the occurrence of macrometastases in 4T1 model. Evaluation of immune subpopulations by flow cytometry revealed that the P. nigrum extract significantly increases the frequency of dendritic cells and activated CD8+ T cells and decreases the frequency of myeloid-derived suppressor like cells and Tregs in the tumor microenvironment of both models but with different dynamics. Our findings strongly suggest that the P. nigrum extract exerts immunomodulatory functions, slightly related to the modulation of cellular energy metabolism, which could ultimately contribute to the promising antitumor effect of P. nigrum.
Subject(s)
Breast Neoplasms , Melanoma, Experimental , Piper nigrum , Mice , Humans , Animals , Female , Breast Neoplasms/pathology , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , CD8-Positive T-Lymphocytes/metabolism , Disease Models, Animal , Melanoma, Experimental/drug therapy , Melanoma, Experimental/pathology , Immunity , Tumor MicroenvironmentABSTRACT
Leukemic cells acquire complex and often multifactorial mechanisms of resistance to treatment, including various metabolic alterations. Although the use of metabolic modulators has been proposed for several decades, their use in clinical practice has not been established. Natural products, the so-called botanical drugs, are capable of regulating tumor metabolism, particularly in hematopoietic tumors, which could partly explain the biological activity attributed to them for a long time. This review addresses the most recent findings relating to metabolic reprogramming-Mainly in the glycolytic pathway and mitochondrial activity-Of leukemic cells and its role in the generation of resistance to conventional treatments, the modulation of the tumor microenvironment, and the evasion of immune response. In turn, it describes how the modulation of metabolism by plant-derived extracts can counteract resistance to chemotherapy in this tumor model and contribute to the activation of the antitumor immune system.
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INTRODUCTION: Regulatory T cells (Treg cells) in a tumor environment and the expression of forkhead box P3 (FOXP3) in tumor cells have been associated with a poor prognosis. There are few studies evaluating Treg cells and FOXP3 in B-cell acute lymphoblastic leukemia (B-cell ALL). This study aimed to evaluate the frequencies of Treg cells in bone marrow (BM) and peripheral blood (PB) of patients with B-cell ALL and to determine their associations with the circulating cytokine profile and the expression of CXCR1 (IL-8 receptor) in Treg cells, as well as to compare FOXP3 expression in blasts of patients with B-cell ALL and normal lymphoid precursors. METHODS: Samples of BM and PB from patients with B-cell ALL and healthy controls were studied. Treg cells, cytokines, FOXP3 and CXCR1 were evaluated using flow cytometry and analyzed. RESULTS: A total of 20 patients with B-cell ALL and 10 healthy controls were included. In B-cell ALL patients, Treg cell frequencies increased significantly, with higher percentages in the PB. Absolute Treg cell counts were associated with absolute blast counts in the BM and PB and with an IL-8 concentration. The IL-8 and IL-6 levels were associated with the CXCR1 expression in PB Treg cells. In addition, a greater expression of FOXP3 was observed in leukemic blasts than in normal lymphoid precursors. CONCLUSIONS: These results suggest that the presence of Treg cells and cytokines in the tumor environment may correspond to mechanisms to evade the immune response. For that reason, it would be important to monitor these parameters in B-cell ALL to establish their effect on the disease prognosis.
ABSTRACT
During carcinogenesis, the microenvironment plays a fundamental role in tumor progression and resistance. This tumor microenvironment (TME) is characterized by being highly immunosuppressive in most cases, which makes it an important target for the development of new therapies. One of the most important groups of cells that orchestrate immunosuppression in TME is myeloid-derived suppressor cells (MDSCs), which have multiple mechanisms to suppress the immune response mediated by T lymphocytes and thus protect the tumor. In this review, we will discuss the importance of modulating MDSCs as a therapeutic target and how the use of natural products, due to their multiple mechanisms of action, can be a key alternative for modulating these cells and thus improve response to therapy in cancer patients.
Subject(s)
Biological Products , Myeloid-Derived Suppressor Cells , Neoplasms , Humans , Biological Products/therapeutic use , Tumor Microenvironment , Immunosuppression TherapyABSTRACT
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.
ABSTRACT
P2Et is the standardized extract of Caesalpinia spinosa (C. spinosa), which has shown the ability to reduce primary tumors and metastasis in animal models of cancer, by mechanisms involving the increase in intracellular Ca++, reticulum stress, induction of autophagy, and subsequent activation of the immune system. Although P2Et has been shown to be safe in healthy individuals, the biological activity and bioavailability can be increased by improving the dosage form. This study investigates the potential of a casein nanoparticle for oral administration of P2Et and its impact on treatment efficacy in a mouse model of breast cancer with orthotopically transplanted 4T1 cells. Animals were treated with either free or encapsulated oral P2Et orally or i.p. Tumor growth and macrometastases were evaluated. All P2Et treatments significantly delayed tumor growth. The frequency of macrometastasis was reduced by 1.1 times with P2Et i.p., while oral P2Et reduced it by 3.2 times and nanoencapsulation reduced it by 3.57 times. This suggests that nanoencapsulation led to higher doses of effective P2Et being delivered, slightly improving bioavailability and biological activity. Therefore, the results of this study provide evidence to consider P2Et as a potential adjuvant in the treatment of cancer, while the nanoencapsulation of P2Et provides a novel perspective on the delivery of these functional ingredients.
ABSTRACT
Interactions in the tumor microenvironment (TME) between tumor cells and stromal cells such as cancer-associated fibroblasts (CAF) favor increased survival, progression, and transformation of cancer cells by activating mechanisms of invasion and metastasis. The design of new therapies to modulate or eliminate the CAF phenotype or functionality has been the subject of recent research including natural product-based therapies. We have previously described the generation of a standardized extract rich in polyphenols obtained from the Caesalpinia spinosa plant (P2Et), which present antitumor activities in breast cancer and melanoma models through activities that modulate the metabolism of tumor cells or induce the development of the immune response. In this work, a model of CAF generation was initially developed from the exposure of 3T3 fibroblasts to the cytokine TGFß1. CAF-like cells generated in this way exhibited changes in the expression of Caveolin-1 and α-SMA, and alterations in glucose metabolism and redox status, typical of CAFs isolated from tumor tissues. Then, P2Et was shown to counteract in vitro-induced CAF-like cell generation, preventing caveolin-1 loss and attenuating changes in glucose uptake and redox profile. This protective effect of P2Et translates into a decrease in the functional ability of CAFs to support colony formation and migration of 4T1 murine breast cancer tumor cells. In addition to the functional interference, the P2Et extract also decreased the expression of genes associated with the epithelial-mesenchymal transition (EMT) and functional activities related to the modulation of the cancer stem cells (CSC) population. This work is an in vitro approach to evaluate natural extracts' effect on the interaction between CAF and tumor cells in the tumor microenvironment; thus, these results open the chance to design a more profound and mechanistic analysis to explore the molecular mechanisms of P2Et multimolecular activity and extent this analysis to an in vivo perspective. In summary, we present here a standardized polymolecular natural extract that has the potential to act in the TME by interfering with CAF generation and functionality.
ABSTRACT
The main limits of current antitumor therapies are chemoresistance, relapses, and toxicity that impair patient quality of life. Therefore, the discovery of therapeutic alternatives, such as adjuvants to conventional therapy that modulate the intracellular oxidation state or the immune response, remains a challenge. Owing to traditional medicine, several uses of plants are known, indicating a promising antitumor and immunomodulatory effect. We evaluated the effect of ethanolic extract of T. usneoides in vitro and in vivo in models of 4T1 breast cancer and B16-F10 melanoma. In vitro evaluations with both cell lines showed that the extract has cytotoxic activity and induces apoptotic cell death. However, its effect on ROS production and glucose uptake was opposite. In vivo, only in the 4T1 model, a significant decrease in tumor size was found in animals treated with the extract, accompanied by an increase in dendritic cells and activated CD8+ T cells, and a decrease in myeloid-derived suppressor-like cells (MDSC-LC) and Tregs in the tumor microenvironment. These results suggest that T. usneoides extract antagonistically regulates tumor metabolism of 4T1 vs. B16-F10, impacting the tumor microenvironment and effective antitumor immune response, leading to a reduction in 4T1 tumor size but not on B16-F10.
ABSTRACT
Background: It has been proposed that polyphenols can be used in the development of new therapies against COVID-19, given their ability to interfere with the adsorption and entrance processes of the virus, thus disrupting viral replication. Seeds from Caesalpinia spinosa, have been traditionally used for the treatment of inflammatory pathologies and respiratory diseases. Our team has obtained an extract called P2Et, rich in polyphenols derived from gallic acid with significant antioxidant activity, and the ability to induce complete autophagy in tumor cells and reduce the systemic inflammatory response in animal models. Methods: In this work, a phase II multicenter randomized double-blind clinical trial on COVID-19 patients was designed to evaluate the impact of the P2Et treatment on the clinical outcome and the immunological parameters related to the evolution of the disease. The Trial was registered with the number No. NCT04410510*. A complementary study in an animal model of lung fibrosis was carried out to evaluate in situ lung changes after P2Et in vivo administration. The ability of P2Et to inhibit the viral load of murine and human coronaviruses in cellular models was also evaluated. Results: Patients treated with P2Et were discharged on average after 7.4 days of admission vs. 9.6 days in the placebo group. Although a decrease in proinflammatory cytokines such as G-CSF, IL-15, IL-12, IL-6, IP10, MCP-1, MCP-2 and IL-18 was observed in both groups, P2Et decreased to a greater extent G-CSF, IL-6 and IL-18 among others, which are related to lower recovery of patients in the long term. The frequency of T lymphocytes (LT) CD3+, LT double negative (CD3+CD4-CD8-), NK cells increased in the P2Et group where the population of eosinophils was also significantly reduced. In the murine bleomycin model, P2Et also reduced lung inflammation and fibrosis. P2Et was able to reduce the viral replication of murine and human coronaviruses in vitro, showing its dual antiviral and anti-inflammatory role, key in disease control. Conclusions: Taken together these results suggest that P2Et could be consider as a good co-adjuvant in the treatment of COVID-19. Clinical trail registration: https://clinicaltrials.gov/ct2/show/NCT04410510, identifier: NCT04410510.
ABSTRACT
Neoadjuvant chemotherapy (NAT) in breast cancer (BC) has been used to reduce tumor burden prior to surgery. However, the impact on prognosis depends on the establishment of Pathological Complete Response (pCR), which is influenced by tumor-infiltrating lymphocyte levels and the activation of the antitumor immune response. Nonetheless, NAT can affect immune infiltration and the quality of the response. Here, we showed that NAT induces dynamic changes in the tumor microenvironment (TME). After NAT, an increase of regulatory T cells and a decrease of CD8+ T cells was found in tumor, correlated with the presence of metastatic cells in lymph nodes. In addition, an increase of polymorphonuclear myeloid-derived suppressor like cells was found in luminal patients post-NAT. pCR patients showed a balance between the immune populations, while non-pCR patients presented an inverse relationship in the frequency of CD68+ versus CD3+, CD8+, and CD20+ cells. Moreover, activated T cells were found in peripheral blood, as well as an increase in T cell clonality with a lower diversity post-NAT. Overall, these results shown that NAT induces an activation of immune response, however, a balance in the TME seems to be related to a better antigenic presentation and therefore a better response to treatment.
Subject(s)
Breast Neoplasms , Neoadjuvant Therapy , Breast Neoplasms/pathology , CD8-Positive T-Lymphocytes , Female , Humans , Lymphocytes, Tumor-Infiltrating , Neoadjuvant Therapy/methods , Tumor MicroenvironmentABSTRACT
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 600 mg/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 600 mg/d. There was no severe toxicity; most of the adverse events were mild, without significant changes in the safety parameters evaluated.
ABSTRACT
PD-1/PD-L1 pathway plays a role in inhibiting immune response. Therapeutic antibodies aimed at blocking the PD-1/PD-L1 interaction have entered clinical development and have been approved for a variety of cancers. However, the clinical benefits are reduced to a group of patients. The research in combined therapies, which allow for a greater response, is strongly encouraging. We previously characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) with antitumor activity in both melanoma and breast carcinoma, as well as immunomodulatory activity. We hypothesize that the combined treatment with P2Et and anti-PD-L1 can improve the antitumor response through an additive antitumor effect. We investigated the antitumor and immunomodulatory activity of P2Et and anti-PD-L1 combined therapy in B16-F10 melanoma and 4T1 breast carcinoma. We analyzed tumor growth, hematologic parameters, T cell counts, cytokine expression, and T cell cytotoxicity. In the melanoma model, combined P2Et and anti-PD-L1 therapy has the following effects: decrease in tumor size; increase in the number of activated CD4+ and CD8+ T cells; decrease in the number of suppressor myeloid cells; increase in PD-L1 expression; decrease in the frequency of CD8+ T cell expressing PD-1; improvement in the cytotoxic activity of T cells; and increase in the IFN γ secretion. In the breast cancer model, P2Et and PD-L1 alone or in combination show antitumor effect with no clear additive effect. This study shows that combined therapy of P2Et and anti-PD-L1 can improve antitumor response in a melanoma model by activating the immune response and neutralizing immunosuppressive mechanisms.