Cervical Cancer Cells Use the CD95 and IL-2 Pathways to Promote Their Proliferation and Survival.

Cervical cancer is a global health problem; therapies focused on eliminating tumour cells and strengthening different immunotherapies are in development. However, it has been observed that cervical tumour cells can evade cell death mechanisms and generate immune system molecules to promote their proliferation and metastasis. In this context, we analysed the role of the IL-2 and CD95 pathways, essential molecules in activating the immune system and eliminating tumour cells.

STAT5 Is Necessary for the Metabolic Switch Induced by IL-2 in Cervical Cancer Cell Line SiHa.

The tumor cells reprogram their metabolism to cover their high bioenergetic demands for maintaining uncontrolled growth. This response can be mediated by cytokines such as IL-2, which binds to its receptor and activates the JAK/STAT pathway. Some reports show a correlation between the JAK/STAT pathway and cellular metabolism, since the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of genes related to energetic metabolism.

Anti-cancer potential of casein and its derivatives: novel strategies for cancer treatment.

Cancer is one of the leading causes of death worldwide, with over 10 million fatalities annually. While tumors can be surgically removed and treated with chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or combined therapies, current treatments often result in toxic side effects in normal tissue. Therefore, researchers are actively seeking ways to selectively eliminate cancerous cells, minimizing the toxic side effects in normal tissue.

Adenosine increases PD-L1 expression in mesenchymal stromal cells derived from cervical cancer through its interaction with AR/AR and the production of TGF-β1.

Mesenchymal stromal cells (MSCs) together with malignant cells present in the tumor microenvironment (TME), participate in the suppression of the antitumor immune response through the production of immunosuppressive factors, such as transforming growth factor beta 1 (TGF-β1). In previous studies, we reported that adenosine (Ado), generated by the adenosinergic activity of cervical cancer (CeCa) cells, induces the production of TGF-β1 by interacting with AR/AR. In the present study, we provide evidence that Ado induces the production of TGF-β1 in MSCs derived from CeCa tumors (CeCa-MSCs) by interacting with both receptors and that TGF-β1 acts in an autocrine manner to induce the expression of programmed death ligand 1 (PD-L1) in CeCa-MSCs, resulting in an increase in their immunosuppressive capacity on activated CD8+ T lymphocytes.

Adenosine Increases the Immunosuppressive Capacity of Cervical Cancer Cells by Increasing PD-L1 Expression and TGF-β Production through Its Interaction with AR/AR.

The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with AR/AR and that TGF-β1 acts in an autocrine manner to induce PD-L1 expression, enhancing the immunosuppressive effects of CeCa cells on activated T lymphocytes (ATLs) and CD8+ cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from E6 and E7 proteins of HPV-16. Interestingly, the addition of the antagonists ZM241385 and MRS1754, which are specific for AR and AR, respectively, or SB-505124, which is a selective TGF-β1 receptor inhibitor, to CeCa cell cultures significantly inhibited PD-L1 expression. In addition, supernatants from CeCa cells that were treated with Ado (CeCa-Ado Sup) increased the expression of PD-1, TGF-β1, and IL-10 and decreased the expression of IFN-γ in ATLs.

Role of SIRT1 in Chemoresistant Leukemia.

Leukemias of the AML, CML, and CLL types are the most common blood cancers worldwide, making them a major global public health problem. Furthermore, less than 24% of patients treated with conventional chemotherapy (low-risk patients) and 10-15% of patients ineligible for conventional chemotherapy (high-risk patients) survive five years. The low levels of survival are mainly due to toxicity and resistance to chemotherapy or other medication, the latter leading to relapse of the disease, which is the main obstacle to the treatment of leukemia.

Immune microenvironment of cervical cancer and the role of IL-2 in tumor promotion.

The tumor microenvironment (TME) is a heterogeneous mixture of resident and tumor cells that maintain close communication through their secretion products. The composition of the TME is dynamic and complex among the different types of cancer, where the immune cells play a relevant role in the elimination of tumor cells, however, under certain circumstances they contribute to tumor development. In cervical cancer (CC) the human papilloma virus (HPV) shapes the microenvironment in order to mediate persistent infections that favors transformation and tumor development.

Inhibition of CD73 expression or A2AR blockade reduces MRP1 expression and increases the sensitivity of cervical cancer cells to cisplatin.

Recently, a link between the biological activity of CD73 in solid tumors and multidrug resistance protein (MRP) has been proposed. Cisplatin (CP) is the most widely used anticancer agent to treat advanced and recurrent cervical cancer (CC). However, multidrug resistance protein-1 (MRP1) is overexpressed in approximately 85% of these tumors and has been strongly associated with cisplatin resistance (CPR).

Fruit Extract of (Lira & F. Chiang) Induces Apoptosis in the Human Cervical Cancer HeLa Cell Line.

(Cucurbitaceae) is a commercial species of chayote and is just one of several species in the genus Sechium, whose extracts inhibit proliferation in tumor cell lines. The capacity of the wild species (SCH) as an antitumor agent is unknown, as is the mechanism of action. In the present study, HeLa cervical cancer and HaCaT normal cell lines were treated with SCH and cell proliferation was inhibited in both cell lines in a dose-dependent manner similar to the effect of the antineoplastic agent cisplatin (Cis).

Evidence that cervical cancer cells cultured as tumorspheres maintain high CD73 expression and increase their protumor characteristics through TGF-β production.

Recently, a link between the biological activity of CD73 and tumorigenicity in solid tumors has been proposed. We previously reported that the generation of adenosine (Ado) by the activity of CD73 in cervical cancer (CC) cells induces transforming growth factor-beta 1 (TGF-β1) production to maintain CD73 expression. In the present study, we analyzed the participation of TGF-β1 in CD73 expression and the development of protumoral characteristics in CaSki CC cells cultured as tumorspheres (CaSki-T) and in monolayers (CaSki-M).

Inhibition of adenosine deaminase activity reverses resistance to the cytotoxic effect of high adenosine levels in cervical cancer cells.

Adenosine (ADO) generation in the tumor microenvironment (TME) plays important roles in the promotion of tumor growth, invasion, and metastasis and in suppression of the antitumor immune response. Recently, adenosine deaminase (ADA) activity in the TME has been proposed to be a compensatory mechanism against toxic accumulation of ADO in cancerous tissues. In the present study, the expression and functional activity of ADA in cervical cancer (CeCa) tumor cells were analyzed: C33A (HPV-), CaSki (HPV + ), and HeLa (HPV + ) cells.

Sodium Caseinate in Combination With Daunorubicin or Cytarabine Improves Survival of Mice With Long-established Leukemia.

Background/aim: Although acute myeloid leukemia (AML) has traditionally been considered an oncological emergency and initiation of therapy is believed to be crucial to minimizing disease-related morbidity and mortality, it has also been suggested that a certain delay in treatment has no negative consequences in terms of response, early mortality, or survival. We aimed to determine the effect of administration of sodium caseinate (SC), a salt of casein, the main milk protein, with cytarabine or with daunorubicin on survival in mice with well-established leukemia.

Materials And Methods: To assay the time of establishment of leukemia in the bone marrow, Balb/c mice were inoculated with 2.

Mutations in the helix αC of the catalytic domain from the EGFR affect its activity in cervical cancer cell lines.

The EGFR is a protein that belongs to the ErbB family of tyrosine kinase receptors. The EGFR is often overexpressed in human carcinomas. Amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain occur in patients with cancer.

Evidence that the viral oncoproteins E6 and E7 of HPV induce the expression of a functional IL-2R on cervical cancer cells.

HPV-positive (HPV+) cervical cancer (CC) cells have been reported to express the IL-2 receptor (IL-2R) in contrast to virus-negative CC cells. This work was carried out to evaluate whether HPV infection induces IL-2R expression in CC cells. The analysis of the IL-2R expression data collected from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) using the Xena platform demonstrate a higher expression of IL-2R subunits in CC tumors in comparison with normal tissues.

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review.

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation.

Improved Survival of Leukemic Mice Treated with Sodium Caseinate in Combination with Daunorubicin without Toxicity.

In recent years, low doses of chemotherapy have been resumed and explored for the treatment of acute myeloid leukemia. Thus, CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, was approved by the US Food and Drug Administration, to deliver a synergistic 5 : 1 molar drug ratio into leukemia cells to a greater extent than normal bone marrow cells and significantly enhance survival compared with conventional treatment in older and newly diagnosed AML patients, but overall survival rate remains low; therefore, the need for new therapeutic options continues. Sodium caseinate (SC), a salt of casein, the main milk protein, has cytotoxic effect in leukemia cell lines, but promotes proliferation of hematopoietic normal cells, while its administration in leukemic mice promotes survival for more than 40 days, but bone marrow surviving mice still harbour leukemic cells, but it is not known whether the combination with cytarabine or daunorubicin can improve survival without damaging normal hematopoietic cells.

Detection of CD39 and a Highly Glycosylated Isoform of Soluble CD73 in the Plasma of Patients with Cervical Cancer: Correlation with Disease Progression.

Persistent infection with high-risk human papillomavirus (HR-HPV) is the main factor in the development of cervical cancer (CC). The presence of immunosuppressive factors plays an important role in the development of this type of cancer. To determine whether CD39 and CD73, which participate in the production of immunosuppressive adenosine (Ado), are involved in the progression of CC, we compared the concentrations and hydrolytic activity of these ectonucleotidases in platelet-free plasma (PFP) samples between patients with low-grade squamous intraepithelial lesions (LSILs) ( = 18), high-grade squamous intraepithelial lesions (HSILs) ( = 12), and CC ( = 19) and normal donors (NDs) ( = 15).

Adenosine augments the production of IL-10 in cervical cancer cells through interaction with the A adenosine receptor, resulting in protection against the activity of cytotoxic T cells.

Cervical cancer (CeCa) produces large amounts of IL-10, which downregulates the major histocompatibility complex class I molecules (HLA-I) in cancer cells and inhibits the immune response mediated by cytotoxic T lymphocytes (CTLs). In this study, we analyzed the ability of CeCa cells to produce IL-10 through the CD73-adenosine pathway and its effect on the downregulation of HLA-I molecules to evade CTL-mediated immune recognition. CeCa cells cultured in the presence of ≥10 µM AMP or adenosine produced 4.

Apoptotic, necrotic, and antiproliferative activity of diosgenin and diosgenin glycosides on cervical cancer cells.

(25R)-spirost-5-en-3β-ol, also known as diosgenin (DSG), exerts antiproliferative activity on diverse cell lines, induces apoptosis, and acts as a chemopreventative agent. However, the relationship between DSG glycosides and apoptotic, necrotic, and antiproliferative activity remains unclear. It is in this regard that we report the antiproliferative, necrotic, and apoptotic activities of DSG and its glycoside derivatives: (25R)-spirost-5-en-3β-yl O-β-D-glucopyranoside (3GD), (25R)-spirost-5-en-3β-yl O-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranoside (3GRD); and (25R)-spirost-5-en-3β-yl O-α-L-rhamnopyranosyl-(1 → 2)-O-[α-L-rhamnopyranosyl-(1 → 4)]-β-D-glucopyranoside), also known as dioscin (DSC), in in vitro assays of cervical HeLa and CaSki cancer cells.

IL-2 Induces Transient Arrest in the G1 Phase to Protect Cervical Cancer Cells from Entering Apoptosis.

Interleukin 2 (IL-2) has been used for the treatment of different types of cancer that express the IL-2 receptor (IL-2R). However, the effect of IL-2 on cervical cancer cells is unknown. IL-2R is present in normal cells of the immune system but not in the healthy cervix.

Casein and Peptides Derived from Casein as Antileukaemic Agents.

Milk is a heterogeneous lacteal secretion mixture of numerous components that exhibit a wide variety of chemical and functional activities. Casein, the main protein in milk, is composed of -, -, and -caseins, each of which is important for nutritional value and for promoting the release of cytokines, also are linked to the regulation of haematopoiesis and immune response and inhibit the proliferation and induce the differentiation of leukaemia cells. It has been shown that the digestive process of caseins leads to the release of bioactive peptides that are involved in the regulation of blood pressure and the inhibition or activation of the immune response by serving as agonists or antagonists of opioid receptors, thus controlling the expression of genes that exert epigenetic control.

El Sodium caseinate and alfa-casein inhibit proliferation of the mouse myeloid cell line 32D clone 3 (32Dcl3) via TNF-α.

Introduction: Sodium caseinate (CS) and its components (alpha-casein, beta-casein, and kappa-casein) have been shown to inhibit the proliferation of the mouse hematopoietic 32D clone 3 (32Dcl3) cell line and induce its differentiation into macrophages. It is well-known that alpha-casein induces IL-1β production and that this cytokine inhibits the proliferation via the production of tumor necrosis factor alpha (TNF-alpha), but it is not known if CS and the caseins inhibit the proliferation via TNF-alpha production. Objective: To evaluate if CS and alpha-casein, beta-casein and kappa-casein inhibit the proliferation on 32Dcl3 cell line via TNF-alpha.

HPV-16 Infection Is Associated with a High Content of CD39 and CD73 Ectonucleotidases in Cervical Samples from Patients with CIN-1.

The development of cervical cancer (CeCa) is associated with high-risk human papilloma virus (HR-HPV) infections, mainly HPV-16, which is present in more than 50% of cases. The presence of immunosuppressive factors in the early stages of the disease is also strongly linked to CeCa progression. In this context, it is unknown whether ectonucleotidases CD39 and CD73, which are involved in the production of adenosine (Ado) that suppresses the specific antitumor immune response, are present in precursor lesions of CeCa.