Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts.

Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals.

Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC.

Genetic Signature of Human Pancreatic Cancer and Personalized Targeting.

Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent.

Exploring monocarboxylate transporter inhibition for cancer treatment.

Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane.

The Relationship between Trop-2, Chemotherapeutic Drugs, and Chemoresistance.

Trop-2 is a highly conserved one-pass transmembrane mammalian glycoprotein that is normally expressed in tissues such as the lung, intestines, and kidney during embryonic development. It is overexpressed in many epithelial cancers but is absent in non-epithelial tumors. Trop-2 is an intracellular calcium signal transducer that participates in the promotion of cell proliferation, migration, invasion, metastasis, and probably stemness.

Earlier Diagnosis of Pancreatic Cancer: Is It Possible?

Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation.

Role of pH in Regulating Cancer Pyrimidine Synthesis.

Replication is a fundamental aspect of cancer, and replication is about reproducing all the elements and structures that form a cell. Among them are DNA, RNA, enzymes, and coenzymes. All the DNA is doubled during each S (synthesis) cell cycle phase.

The complex relationship between multiple drug resistance and the tumor pH gradient: a review.

Multiple drug resistance (MDR) is the tumor's way of escaping the cytotoxic effects of various unrelated chemotherapeutic drugs. It can be either innate or acquired. MDR represents the end of the therapeutic pathway, and it practically leaves no treatment alternatives.

Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease.

Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions.

The flavonoid silymarin extracted from the seeds of is a mixture of 6 flavolignan isomers. The 3 more important isomers are silybin (or silibinin), silydianin, and silychristin. Silybin is functionally the most active of these compounds.

Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches.

Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient.

Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years.

Targeting the pH Paradigm at the Bedside: A Practical Approach.

The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief.

The Ph paradigm in cancer.

Malignant tissues show a peculiar feature regarding pH: while normal tissues have a higher extracellular pH than intracellular pH, in cancer is exactly the opposite. This phenomenon is called the inversion of the pH gradient and is now considered a hallmark of malignancy. For some time, this inverted pH gradient was believed to be a secondary effect of cancer.

Synergy Between Low Dose Metronomic Chemotherapy and the pH-centered Approach Against Cancer.

Low dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering vascular endothelial growth factor (VEGF) and increasing trombospondin-1 (TSP1). It has also been adopted as a compassionate treatment in very advanced human cancer.

Triple-edged therapy targeting intracellular alkalosis and extracellular acidosis in cancer.

Extracellular acidity and intracellular alkalinity are two of the characteristics hallmarks of malignant cells and their environment. This involves an inversion of the extracellular/intracellular pH gradient when compared with normal cells and it gives malignant cells proliferative and invasive advantages. Thus, the reversal of the pH gradient is a legitimate objective in the treatment of cancer and may be accomplished with drugs already used for other purposes and/or with specific new drugs that are currently being studied.

Cancer: fundamentals behind pH targeting and the double-edged approach.

The highly regulated pH of cells and the less-regulated pH of the surrounding extracellular matrix (ECM) is the result of a delicate balance between metabolic processes and proton production, proton transportation, chemical buffering, and vascular removal of waste products. Malignant cells show a pronounced increase in metabolic processes where the 10- to 15-fold rise in glucose consumption is only the tip of the iceberg. Aerobic glycolysis (Warburg effect) is one of the hallmarks of cancer metabolism that implies excessive production of protons, which if stayed inside the cells would result in fatal intracellular acidosis (maintaining a strict acid-base balance is essential for the survival of eukaryotic cells).

Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity.

Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature.

Methods: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed.

Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs.

Objective: To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties.

Material And Methods: A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings.

Clusterin: a key player in cancer chemoresistance and its inhibition.

Clusterin is a heterodimeric disulfide-linked glycoprotein (449 amino acids) isolated in the rat prostate after castration. It is widely distributed in different tissues and highly conserved in species. There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis.