346 research outputs found
Two preclinical tests to evaluate anticancer activity and to help validate drug candidates for clinical trials.
Current approaches to assessing preclinical anticancer activity do not reliably predict drug efficacy in cancer patients. Most of the compounds that show remarkable anticancer effects in preclinical models actually fail when tested in clinical trials. We blame these failures on the complexity of the disease and on the limitations of the preclinical tools we require for our research. This manuscript argues that this lack of clinical response may also be caused by poor in vitro and in vivo preclinical designs, in which cancer patients' needs are not fully considered. Then, it proposes two patient-oriented tests to assess in vitro and in vivo anticancer activity and to help validate drug candidates for clinical evaluation
Understanding why aspirin prevents cancer and why consuming very hot beverages and foods increases esophageal cancer risk. Controlling the division rates of stem cells is an important strategy to prevent cancer.
Cancer is, in essence, a stem cell disease. The main biological cause of cancer is that stem cells acquire DNA alterations during cell division. The more stem cell divisions a tissue accumulates over a lifetime, the higher is the risk of cancer in that tissue. This explains why cancer is diagnosed millions of times more often in some tissues than in others, and why cancer incidence increases so dramatically with age. It may also explain why taking a daily low-dose aspirin for several years reduces the risk of developing and dying from cancer. Since aspirin use reduces PGE2 levels and PGE2 fuels stem cell proliferation, aspirin may prevent cancer by restricting the division rates of stem cells. The stem cell division model of cancer may also explain why regular consumption of very hot foods and beverages increases the risk of developing esophageal cancer. Given that tissue injury activates stem cell division for repair, the thermal injury associated with this dietary habit will increase esophageal cancer risk by inducing the accumulation of stem cell divisions in the esophagus. Using these two examples, here I propose that controlling the division rates of stem cells is an essential approach to preventing cancer
The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis.
Cancers of unknown primary site are metastatic cancers for which primary tumors are not found after detailed investigations. In many cases, the site of origin is not identified even on postmortem examination. These cancers are the fourth most common cause of cancer death. The biological events involved in the development of this type of cancers remain unknown. This manuscript discusses that, like metastatic cells, stem cells have a natural ability to migrate. A cancer of unknown primary site would form when deregulated, premalignant or cancerous stem cells migrated away from their natural tissue and gave rise to a cancer in a new site before or without generating a tumor in their original tissue. It is important to realize that forming a tumor in a tissue is not a prerequisite for stem cells to migrate away from that tissue. This view is in accordance with recent observations that strongly support the tumorigenesis model in which cancer arises from normal stem cells. Evidence has accumulated that cancer stem cells may play a key role in cancer progression and resistance to therapy. Successful treatment of cancer, including that of unknown primary site, may therefore require the development of therapies against cancer stem cells
Selective amino acid restriction therapy (SAART): a non-pharmacological strategy against all types of cancer cells
Metastasis will continue to be an incurable disease for most patients until we develop highly selective anticancer therapies. The development of these therapies requires finding and exploiting major differences between cancer cells and normal cells. Although the sum of the many DNA alterations of cancer cells makes up such a major difference, there is currently no way of exploiting these alterations as a whole. Here I propose a non-pharmacological strategy to selectively kill any type of cancer cell, including cancer stem cells, by exploiting their complete set of DNA alterations. It is based on creating challenging environmental conditions that only cells with undamaged DNAs can overcome. Cell survival requires continuous protein synthesis, which in turn requires adequate levels of 20 amino acids (AAs). If we temporarily restrict specific AAs and keep high levels of others whose deficit triggers proteolysis, we will force cells to activate a variety of genetic programs to obtain adequate levels of each of the 20 proteinogenic AAs. Because cancer cells have an extremely altered DNA that has evolved under particular environmental conditions, they may be unable to activate the genetic programs required to adapt to and survive the new environment. Cancer patients may be successfully treated with a protein-free artificial diet in which the levels of specific AAs are manipulated. Practical considerations for testing and implementing this cheap and universal anticancer strategy are discussed
A local mechanism by which alcohol consumption causes cancer
Epidemiological data indicate that 5.8% of cancer deaths world-wide are attributable to alcohol consumption. The risk of cancer is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mostly produced in the liver, it is not clear why alcohol use preferentially exerts a local carcinogenic effect. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages; however, this effect may have been overlooked because dead cells cannot give rise to cancer. Here I discuss that the cytotoxic effect of ethanol on the cells lining the oral cavity, pharynx and esophagus activates the division of the stem cells located in deeper layers of the mucosa to replace the dead cells. Every time stem cells divide, they become exposed to unavoidable errors associated with cell division (e.g., mutations arising during DNA replication and chromosomal alterations occurring during mitosis) and also become highly vulnerable to the genotoxic activity of DNA-damaging agents (e.g., acetaldehyde and tobacco carcinogens). Alcohol consumption may increase the risk of developing cancer of the oral cavity, pharynx and esophagus by promoting the accumulation of cell divisions in the stem cells that maintain these tissues in homeostasis. Understanding the mechanisms of carcinogenicity of alcohol is important to reinforce the epidemiological evidence and to raise public awareness of the strong link between alcohol consumption and cance
Effect of DNA repair deficiencies on the cytotoxicity of resveratrol
Numerous preclinical studies have shown that the
naturally-occurring polyphenol resveratrol may
produce health-beneficial effects in a variety of
disorders, including cancer, diabetes, Alzheimer, and
cardiovascular diseases. Resveratrol has entered
clinical trials for the prevention and treatment of
several of these disorders. This polyphenol is also
available in the market as a dietary supplement.
Experimental data have shown, however, that
resveratrol induces DNA damage in a variety of cells.
Here we review such evidence and evaluate the
cytotoxicity of resveratrol (MTT assay) in cells deficient
in several major DNA repair pathways (i.e.,
homologous recombination, non-homologous end
joining, base excision repair, nucleotide excision repair,
mismatch repair, and Fanconi anemia repair). Cells
deficient in base excision repair (EM9), nucleotide
excision repair (UV4 and UV5) and Fanconi Anemia
(KO40) were slightly hypersensitive to
resveratrol-induced cytotoxicity with respect to their
parental cells (AA8). Our results suggest that these
pathways may participate in the repair of the DNA
damage induced by resveratrol and that deficiencies in
these pathways may confer hypersensitivity to the
genotoxic activity of this dietary constituen
Dietary Manipulation of Amino Acids for Cancer Therapy
Cancer cells cannot proliferate and survive unless they obtain sufficient levels of the 20 proteinogenic amino acids (AAs). Unlike normal cells, cancer cells have genetic and metabolic alterations that may limit their capacity to obtain adequate levels of the 20 AAs in challenging metabolic environments. However, since normal diets provide all AAs at relatively constant levels and ratios, these potentially lethal genetic and metabolic defects are eventually harmless to cancer cells. If we temporarily replace the normal diet of cancer patients with artificial diets in which the levels of specific AAs are manipulated, cancer cells may be unable to proliferate and survive. This article reviews in vivo studies that have evaluated the antitumor activity of diets restricted in or supplemented with the 20 proteinogenic AAs, individually and in combination. It also reviews our recent studies that show that manipulating the levels of several AAs simultaneously can lead to marked survival improvements in mice with metastatic cancers.AMINOVITA PRJ201803388Junta de Andalucía 2017/CTS-657; 2019/CTS-657; 2021/CTS-657AMINOVIT
Presentación
Presentación del número especial de la revista como consecuencia del décimo aniversario de esta, realizada con las aportaciones de los colaboradores de la revista durante la pandemia
The Cardiac Glycosides Digitoxin, Digoxin and Ouabain Induce a Potent Inhibition of Glycolysis in Lung Cancer Cells
Cardiac glycosides are promising anticancer drugs. We have recently shown that the cardiac glycosides digitoxin, digoxin and ouabain induce selective killing of lung cancer cells, and that the cytotoxicity of digitoxin against these cells occurs at concentrations below those observed in the plasma of cardiac patients treated with this drug (Oncogene, 2013. doi: 10.1038/onc.2013.229). Here we report that digitoxin, digoxin and ouabain induce a potent inhibition of glycolysis (glucose consumption and lactate production) in A549 cells at nanomolar concentrations. This inhibition was comparable to that observed with millimolar concentrations of the glycolysis inhibitor dichloroacetate, which is currently undergoing clinical trials for the treatment of cancer. Because platinum compounds are commonly used in the treatment of lung cancer, we tested the cytotoxicity of several combinations of cisplatin with each cardiac glycoside; these combinations induced synergistic, antagonistic or additive effects mainly depending on the order at which the drugs were added to the cells
Curcumin as a DNA Topoisomerase II Poison
Curcumin, the major active component of the spice
turmeric, is recognised as a safe compound with great
potential for cancer chemoprevention and cancer therapy.
It induces apoptosis, but its initiation mechanism
remains poorly understood. Curcumin has been assessed
on the human cancer cell lines, TK-10, MCF-7 and UACC62, and their IC50 values were 12.16, 3.63, 4.28 mM
respectively. The possibility of this compound being a
topoisomerase II poison has also been studied and it was
found that 50 mM of curcumin is active in a similar
fashion to the antineoplastic agent etoposide. These
results point to DNA damage induced by topoisomerase
II poisoning as a possible mechanism by which curcumin
initiates apoptosis, and increase the evidence suggesting
its possible use in cancer therapy.Ministerio de Ciencia y Tecnología de España. SAF 2000-016
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