Get updates. Give today. The other major pathway leading to apoptosis is the intrinsic, or mitochondrial, pathway. Stem cells are particularly vulnerable to developing mutations that might evolve into a malignant clone.
Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?
Therefore, the cells located at the base of crypts, presumably stem cells, are highly prone to apoptosis, able to counteract dangerous mutations [ 19 ]. The result of the imbalance between cell proliferation and apoptosis determines colorectal tumour growth. The molecular mechanisms of cell division and apoptosis are similar in normal and tumour cells, but in tumour cells, these mechanisms are aberrantly regulated. Four cellular functions are inadequate regulated in tumour cells: 1 control of cell proliferation is inefficient; 2 genetic and chromosomal structure is destabilized; 3 cellular differentiation program is frequently altered; 4 the control of apoptosis is disturbed [ 20 ].
Multiple sequential genetic changes are needed to occur in order to ensure colorectal cancer evolution. Gene alterations cause disruption of signalling pathways in which they are involved, accompanied by increased proliferative potential and decreased apoptosis of cells [ 21 ]. Along with genetic mutations, colon carcinogenesis is accompanied by epigenetic changes that lead to altered expression of key genes.
Abnormalities in apoptotic function contribute to both pathogenesis of colorectal cancer, and its resistance to chemotherapeutics and radiotherapy [ 19 ]. Apoptosis is an active, specialized form of cell death with distinct biochemical and genetic pathways that play a critical role in normal tissue homeostasis and development. Under stress, such as precancerous lesions, the mechanisms involved in repairing DNA damage are activated and potentially harmful cells are removed, and carcinogenesis is blocked [ 25 ]. Lack of regulation of the apoptosis pathways may promote tumorigenesis and induce resistance to treatment in cancer cells [ 19 ].
Upon receiving specific signals instructing the cells to undergo apoptosis, the caspase family of proteins is typically activated and cleaves key cellular components required for normal cellular function, including structural proteins in the cytoskeleton and nuclear proteins such as DNA repair enzymes [ 29 ].
Caspases can directly signal apoptosis or use mitochondria as an intermediate and additional point of regulation in apoptosis signalling [ 30 ].
Apoptosis and Its Modulation by Drugs | Ross G. Cameron | Springer
The drop of mitochondrial membrane potential initiates the osmotic swelling of the matrix by water influx and release of cytochrome c from mitochondrial intermembrane space into the cytoplasm. Between the death receptor pathway and the mitochondrial pathway of apoptosis, there is an overlap. Apoptosis is subverted during tumorigenesis through the systematic loss of regulatory control mechanisms, ultimately resulting in the generation of a malignant phenotype and resistance to chemotherapy and radiation therapy.
- Apoptosis in anititumor strategies: Modulation of cell cycle or differentiation?
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Mutations in both Bax and Bak genes confer cells the resistance to apoptosis [ 49 , 50 ]. Decreased Bax expression was correlated with poor prognosis and progression towards metastasis [ 54 ]. One of the best known tumour suppressor proteins is p53 , encoded by the tumour suppressor gene TP53 located on the short arm of chromosome 17 17p Tumour cells presenting p53 mutations are defective in the induction of apoptosis. Inhibitors of apoptosis IAPs family suppress apoptosis through inhibition of effector caspases [ 62 ]. The expression of inhibitor of apoptosis proteins IAPs is dysregulated in colorectal cancer.
Apoptosis-modulating drugs for improved cancer therapy.
During apoptosis process, the caspases implicated are either initiator caspases e. In the initiation and execution of apoptosis, caspases remain important players; therefore, low levels of caspases or impairment in caspase function may lead to a decrease in apoptosis and carcinogenesis [ 66 , 67 ].
More than one caspase can be downregulated, contributing to colon cancer cell growth and development. Signalling via death receptors could be impaired in human cancers via downregulation of receptor surface expression as part of an adaptive stress response. Death receptors and their ligands are key players in the extrinsic pathway of apoptosis. The extrinsic signalling pathway leading to apoptosis involves transmembrane death receptors that are members of the tumour necrosis factor TNF receptor gene superfamily [ 69 ].
Several abnormalities in the death signalling pathways that can lead to evasion of the extrinsic pathway of apoptosis have been identified: the downregulation of receptor expression, the impairment of its function, as well as a reduced level in the death signals, all of which contribute to impaired signalling and a reduction of apoptosis. Reduced membrane expression of death receptors and abnormal expression of decoy receptors have also been reported to play a role in the evasion of the death signalling pathways in various cancers [ 12 , 70 ] Figure 1.
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The oxidative stress process is characterized by an increased generation of reactive oxygen species ROS accompanied by a dysfunction of the antioxidant systems which exist in every cell, dependent on the metabolic state of the cell [ 71 , 72 ]. The increased metabolic activity, mitochondrial dysfunction, peroxisome activity, oncogene activity, increased activity of oxidases, cyclooxygenases, lipoxigenases could be responsible for the generation and release of reactive oxygen species in tumour cells [ 73 — 75 ]. When ROS production does not irreversibly alter cell viability, they can act as primary messengers, modulating several intracellular signalling cascades that lead to cancer progression [ 76 ].
High levels of ROS induce cell apoptosis or necrosis by causing an alteration of membrane permeability, a genetic instability, oxidative modifications that lead to less active enzymes or proteins more susceptible to proteolytic degradation [ 77 ]. Excessive production of ROS in tumour cells induces apoptosis or necrosis, and acts as an important inhibitor of cancer cell proliferation.
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Fas ligand mediates the induction of ROS, essential for the initiation of apoptotic signalling cascade and activation of the intrinsic apoptotic machinery by disruption of mitochondrial membrane integrity [ 79 ] Figure 1. The transformed cells use ROS signals to drive proliferation to tumour progression. Tumour cells present an increased basal oxidative stress, making them vulnerable to chemotherapeutic agents that further augment ROS generation or weaken antioxidant defences of the cell [ 80 ].
Reactive oxygen species can act as second messengers in cellular signalling. For example, hydrogen peroxide H 2 O 2 regulates protein activity through reversible oxidation of its targets, including protein tyrosine phosphatases, protein tyrosine kinases, receptor tyrosine kinases and transcription factors [ 85 , 86 ]. Activation of ERK in tumour cells by biocompounds e. Among them, over flavonoids were found in vegetables and fruits, wines, seeds, nuts, grains and teas, herbs, and represent a class of plant secondary metabolites, known for their antioxidant properties [ ].
The position of hydroxyl groups and other features in the chemical structure of flavonoids are important for their antioxidant and free radical scavenging activities [ 70 ]. The dietary compounds could interfere with specific stages of the carcinogenic process, inhibiting cell proliferation and inducing apoptosis in different types of cancer cells [ ]. Since the s, despite extensive clinical trials, mortality from colon cancer is a major public health problem in developed countries as a result of high consumption of animal fat or red meat and low intake of fibres or vegetables [ ].
Protective factors include physical activity and increased intakes of dietary fibre, fish, nuts, dairy products, fruits and vegetables, while other factors, including weight and obesity, waist circumference, smoking, alcohol consumption, and red and processed meat intakes increase the risk of colorectal cancer [ , ]. Over the last decade, different drugs and nutritional elements have been studied in preclinical as well as clinical trials and proved to have potential benefit in the field of CRC prevention [ ].
Chemoprevention, the use of drugs or other agents to inhibit the development or progression of malignant changes in cells represents an alternative approach to reduce the mortality from colorectal cancer as well as other cancers [ ].
Biocompounds—dietary sources and mechanisms of action involved in modulation of apoptosis. It is a strong topoisomerase inhibitor, similarly to etoposide and doxorubicin. It has a wide spectrum of activity, expressed in protecting cells from malignant transformation, reducing proliferation of tumour cells and stimulating apoptosis [ , ]. Young sprouts of broccoli and cauliflower are particularly rich in glucoraphanin.
It is produced when the enzyme myrosinase transforms glucoraphanin, a glucosinolate, into sulforaphane upon damage to the plant which allows the two compounds to mix and react [ ]. However, little is known about the differential effects of SFN on colon cancer and normal cells [ ]. Lycopene is a bright carotenoid pigment and phytochemical found in tomatoes, red carrots, watermelons and papayas. Although lycopene is chemically a carotene, it has no vitamin A activity.
Also foods that are not red may contain lycopene, such as asparagus or parsley. Glucobrassicin is a type of glucosinolate found in cabbages, broccoli, mustards, horseradish and woad. Silibinin is the major active constituent of silymarin , a standardized extract of the milk thistle seeds, that contains a mixture of flavonolignans and was shown to induce apoptosis in colon cancer cells [ , ]. It can be found in grapefruits, oranges and tomatoes skin [ ]. Pomegranate juice obtained from Punica granatum is rich in polyphenol compounds such as gallo, ellagitannin and flavonoid classes.
It was shown that pomegranate juice derivatives promote apoptosis of colon cancer cells by inducing the intrinsic pathway, but no effect was shown on the extrinsic pathway [ ]. Results of clinical trials revealed that colon cancer can be successfully treated by chemotherapy, if the tumour selective detection can be substantial increased.
In this regard, there is an increasing demand for biomarkers for risk assessment, early detection, prognosis and surrogate end points.
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