Both cell-mediated immunotherapy Immunotherapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.Immunotherapy
Full Answer
Is there a role for apoptosis in the treatment of cancer?
Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting apoptosis in cancer is feasible.
What drugs induce apoptosis?
Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Enhancement of CDDP cytotoxicity by caffeine is characterized by apoptotic cell death. Chemotherapy-induced apoptosis in epithelial ovarian cancers.
Does the induction of apoptosis induce cancer treatment?
However, the significance of induction of apoptosis in cancer treatment remains uncertain.
Does the apoptotic pathway play a role in anticancer therapy?
Many of these changes cause intrinsic resistance to the most common anticancer therapy, chemotherapy. Promising new anticancer therapies are plant-derived compounds that exhibit anticancer activity through activating the apoptotic pathway. Keywords: apoptosis, anticancer therapy, curcumin, apoptotic evasion
What increases apoptosis?
Recent studies demonstrated that resveratrol is a potent sensitizer of tumor cells for TRAIL- induced apoptosis through p53-independent induction of p21- and p21-mediated cell cycle arrest (19). EGCG was found to enhance TRAIL-induced apoptosis in hepatocellular carcinoma cell lines (20).
What causes apoptosis in cancer cells?
Apoptosis is either created by death receptors, which are called extrinsic pathway utilizing caspases 8 and 10. The other pathway is mitochondrial path or intrinsic pathway involving caspase 9. Recognizing involved mechanisms in cancer development is of great importance for developing neoplastic treatment.
Does chemotherapy cause apoptosis?
Apoptosis has been considered a major mechanism of chemotherapy-induced cell death, and pathways regulating apoptosis are the focus of many preclinical drug discovery investigations.
Does Herceptin increase apoptosis?
Thus, Herceptin treatment of ErbB2-overexpressing cells can inhibit ErbB2-mediated Cdc2-Tyr-15 phosphorylation and p21(Cip1) up-regulation, which allows effective p34(Cdc2) activation and induction of apoptosis upon Taxol treatment.
What is cancer apoptosis?
(A-pop-TOH-sis) A type of cell death in which a series of molecular steps in a cell lead to its death. This is one method the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells.
What is the importance of apoptosis in cancer treatment?
Apoptosis in Cancer The loss of apoptotic control allows cancer cells to survive longer and gives more time for the accumulation of mutations which can increase invasiveness during tumor progression, stimulate angiogenesis, deregulate cell proliferation and interfere with differentiation [2].
What drugs cause apoptosis?
Studies of the signals which might engage apoptosis, the genes which modulate it and the biochemical process of drug-induced apoptosis itself are described, where possible, for glucocorticoids, topoisomerase inhibitors, alkylating agents, antimetabolites and antihormones.
How do drugs induce apoptosis?
Factors that were critical in drug-induced apoptosis were activation of caspases, with caspase-8 being activated by diverse drugs in a FADD-independent manner. Certain drugs also demonstrated some dependence on FADD in the induction of cell death. Caspase-9 was activated more selectively by chemotherapeutic agents.
Does chemo prevent apoptosis?
Chemotherapeutic drugs induce pro-apoptosis in cancer cells; however, the upregulation of anti-apoptotic proteins, e.g. Bcl-2 and IAPs, would cause cancer resistance. Death receptors including NF-κB-, PI3/AKT-, and p53-related signaling pathways are also involved in the chemoresistance.
Does HER2 cause apoptosis?
There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis.
What is the difference between trastuzumab and pertuzumab?
Pertuzumab is a fully humanized monoclonal antibody which binds to domain II of HER2, essential for dimerization [27, 59], while trastuzumab binds to domain IV. Pertuzumab efficiently inhibits ligand-induced HER2/HER3 dimerization, whereas trastuzumab has only a minor effect in the presence of a ligand.
Is Herceptin the same as trastuzumab?
Herceptin is the brand name of a medicine called trastuzumab. It's used to treat some types of breast cancer, oesophageal cancer and stomach cancer.
What is the role of apoptosis in cell death?
It is particularly critical in long-lived mammals [1] as it plays a critical role in development as well as homeostasis [2]. It serves to eliminate any unnecessary or unwanted cells and is a highly regulated process.
How many caspases are involved in apoptosis?
The caspase protease activity is essential to successful apoptosis as they cleave hundreds of various proteins [3]. There are four initiator caspases (caspase-2, -8, -9, 10) and three executioner caspases (caspase-3, -6, -7) [4]. The executioner caspases cleave the target proteins that eventually leads to the death of the cell.
Why is SMAC released during apoptosis?
SMAC is released during apoptosis to inhibit inhibitor of apoptosis proteins (IAP) so that apoptosis proceeds once the apoptosome is formed [4]. MOMP will also lead to cell death if caspases are not activated. The permeabilization of the membrane leads to loss of mitochondrial function which leads to cell death [3].
What are the caspases that result in cell death?
Caspases-3, -6 and -7 are the executioner caspases that result in cell death. Arrows represent activation and T bars represent inhibition. The extrinsic and intrinsic pathways converge after the activation of caspase-8.
What is the mechanism of death in cancer cells?
Apoptosis, the cell’s natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a wide variety of means including overexpression ...
What is the ability to target and activate an apoptotic pathway?
The ability to target and activate an apoptotic pathway would provide a more universal cancer therapy.
Which pathway is regulated by the B-cell lymphoma-2 (BCL-2) protein family?
The pathways are highly regulated so that apoptosis will only occur if signaled. The intrinsic pathway , in particular, is regulated by the B-cell lymphoma-2 (BCL-2) protein family which include proapoptotic effector proteins, ...
Which gene is involved in apoptosis?
For example, the tumor suppressor gene p53 induces apoptosis by transcriptionally activating the gene for PUMA, which can bind to and antagonize anti-apoptotic Bcl-2 family members ( 41 , 42 ). Bmf and Bim are kept inactive in healthy cells by sequestration on microtubules and myosin, respectively ( 43 , 44 ).
What are the biochemical markers of apoptosis?
Biochemical markers of apoptosis include activation of proteases termed caspases, cleavage of proteins and DNA and exposure of phosphatidylserine on the cell surface.
What is the apoptosis response?
Further complicating the analysis of cell death is the fact that apoptosis is a common response to cell stress ( 9 ). Cells monitor many aspects of their physiology. Any drug or agent that is capable of killing a cell will cause physiological changes when given at sub-lethal doses or in the period before the cell is biochemically inert. When detected by the cell, these changes often elicit some kind of stress response. Some responses, such as production of heat shock proteins, may serve to protect the cell, whereas others, such as activation of the apoptotic process, may hasten its demise. The ability of drugs and toxins with known lethal biochemical activities to nevertheless provoke an apoptotic death response has caused a great deal of confusion in the field.
What is the role of MDM2 in cell cycle arrest?
Novel agents have been developed that bind to MDM2, displacing p53 and thereby activating the p53 pathway, leading to cell cycle arrest and apoptosis ( 108 ). Such agents would have the advantage of not affecting normal cells and would be expected to work well against tumors overexpressing MDM2, but might rapidly select cancer cells that had lost or mutated p53.
What is the most common mutation in human cancer?
p53 is the most commonly mutated gene in human cancers, but precisely how it prevents tumors developing is not certain. Humans heterozygous for loss of function mutations to p53 (Li–Fraumeni syndrome) and mice with one or both alleles of p53 deleted develop cancers at an early age in many different tissues ( 55 , 56 ). p53 has two main functions, it can cause cell cycle arrest by transcriptionally activating the p21 cyclin kinase inhibitor gene ( 57 ) and it can cause apoptosis by transcriptionally activating pro-apoptotic genes, especially for the BH3-only protein PUMA ( 41 , 58 ).
What is BCL-2 antagonist?
Bcl-2 antagonists. Several approaches are being used to promote apoptosis of cancer cells by antagonizing Bcl-2 family members or by reducing their levels. A drug based on an antisense nucleotide to bcl-2 is being trialed in a wide range of different cancers ( 96 ).
What is the most common cancer of blood cells?
The most common cancer of the blood cells in humans is the B cell neoplasia follicular lymphoma. The bcl-2 gene was identified because it lies at the breakpoint of the t (14;18) translocation that is found in most cases. Experiments in vitro showed that Bcl-2 can prevent apoptosis of cells starved of cytokine and revealed it to be the first oncogene that acts by inhibiting cell death rather than by stimulating cell proliferation ( 3 ).
Abstract
Defective apoptosis (programmed cell death) represents a major causative factor in the development and progression of cancer. The ability of tumor cells to evade engagement of apoptosis can play a significant role in their resistance to conventional therapeutic regimens.
Introduction
Until relatively recently, the underlying cause of cancer was attributed to accelerated or dysregulated proliferation leading to cellular expansion and accumulation of tissue mass.
Cancer and Apoptosis: First Principles
Cancer is a highly heterogenous disease, arising from multiple tissue types and displaying great genetic diversity.
Central Biochemical Machinery and Pathways to Death
The unifying features of apoptosis, irrespective of cell type and inducing stimulus, are largely morphological and include chromatin condensation, DNA fragmentation, blebbing of the plasma membrane, and cell shrinkage.
Death Receptor-mediated Apoptosis: The Extrinsic Pathway
The extrinsic pathway to caspase activation can be mediated by one of several death receptors when bound by the appropriate ligand ( 10 ). Currently, the most clearly understood of these pathways is interaction between the Fas receptor and its ligand, FasL, 2 and activation of the TNF-R1 by TNF.
Mitochondria-mediated Apoptosis: The Intrinsic Pathway
The intrinsic mitochondrial pathway is characterized by the rapid release of cytochrome c from the mitochondrial intermembrane space into the cytosol.
Apaf-1-independent Cell Death
A number of recent studies have defined a form of cell death that proceeds independently of Apaf-1 and caspase activation but is subject to regulation by factors typically associated with the apoptotic cascade.
Why is inactivation of apoptosis important?
1 ). So important is this inactivation of apoptosis to cancer development that evasion of apoptosis is considered to be one of the six fundamental hallmarks of cancer 1. A corollary of this is that if the apoptotic pathway inactivated in tumour development is ...
What is the inactivation of apoptosis?
The inactivation of programmed cell death, or apoptosis, is central to the development of cancer. This disabling of apoptotic responses might be a major contributor both to treatment resistance and to the observation that, in many tumours, apoptosis is not the main mechanism for the death of cancer cells in response to common treatment regimens.
How does p53 affect cancer cells?
It is clear from genetic studies with mice that p53 has a key role as a 'guardian of the tissue' by inducing apoptosis to prevent the continued proliferation of cells with defects in DNA repair, in damage checkpoints or in telomere function. To become malignant, therefore, the cell must inactivate the apoptotic pathway. As a consequence of this inactivation, the cancer cell's susceptibility to apoptosis is severely compromised and other forms of death become more important for cell killing and tumour response to DNA-damaging agents. Assays that measure only apoptosis or any other single form of cell killing after treatment with an anticancer agent are likely to give misleading results. However an assay for colony formation can integrate all forms of death and, in most circumstances, gives an accurate picture of overall cell killing that is correlated to tumour response in vivo. Finally, the fact that genes controlling apoptosis might not be as important in determining tumour sensitivity to anticancer treatment as has been thought until recently does not mean that treatment sensitivity is not affected by the cell's genetic makeup. In addition to the many genes affecting different types of DNA repair, which are clearly involved in tumour sensitivity to treatment, many important questions remain as to the genetic determinants of cell death by modes other than apoptosis. Answers to these questions will provide exciting opportunities to exploit differences between normal and malignant tissues to improve cancer therapy.
Why is there no correlation between pro- and anti-apoptotic genes?
Despite the caveats associated with clinical data, it is tempting to conclude that the reason for the lack of correlation of pro- and anti-apoptotic genes with treatment sensitivity is that apoptosis is not the main reason for cell killing by anticancer agents for many tumour types. from this box.
What is the apoptotic response?
The apoptotic response is one that acts to cull cells that are proliferating aberrantly or that have suffered DNA damage, such as through checkpoint or repair defects. Cells with such lesions that also lack p53 proliferate or survive inappropriately, propelling the development of cancer.
What determines the form of cell death induced by a particular anticancer agent?
What determines the form of cell death induced by a particular anticancer agent? The answer is not simple: it depends on the context, including cell type, the genotype of the cell, the type of DNA damage to which the cell is exposed and the dose of the agent used 17. Clearly the situation is more complex than the originally proposed concept that cells either repair their damage or apoptose following treatment with DNA-damaging agents. Instead, it could be argued that apoptosis is just one form of programmed cell death and that the important paradigm shift made a decade ago was that damaged cells initiated a response that, depending of the genetic makeup of the cell and its context, could lead to an active programme of cell death, one outcome of which could be apoptosis. However, cell death, at least after ionizing radiation, can be stochastic, as demonstrated by the data in Fig. 2. Here we show that in human tumour cells that sustain a translocation in chromosome 4 after 5 Gy of radiation, only those with reciprocal translocations are retained, whereas those with non-reciprocal translocations (which produce a dicentric and an acentric fragment), are lost from the population. Why do the cells with the non-reciprocal translocation die whereas those with the reciprocal translocation do not? The precise mechanism has not been established, but it is probably the result of the loss of the large amount of genetic material present in the micronucleus that would be lost from both daughters. In fact, one recent study following the fate of irradiated rat embryo cells expressing MYC by video time lapse demonstrated that 80% of cells that die (that is, did not form colonies) following irradiation contained micronuclei at the first, second or third division after irradiation 22. In addition to micronuclei, cells with non-reciprocal translocations have dicentric chromosomes that lead to anaphase bridges at mitosis and, again, eventual loss of chromosome material. But why do these data indicate that cell killing is stochastic? As the probability of a translocation between two broken chromosomes being either a non-lethal reciprocal or a lethal non-reciprocal exchange is 50:50 and almost certainly random, death in these cell lines after irradiation is probably stochastic. This stochastic nature of cell killing is consistent with the exponential nature of cell survival as a function of dose that has been demonstrated for irradiation and other anticancer agents (see below). However, this does not mean that the sensitivity of cells to anticancer agents is not determined by genetic factors. For example, the many genes that control DNA repair clearly have a major impact on tumour sensitivity to treatment 23, 24, 25.
What are the defects of p53?
Defects in several processes, including DNA double-strand break (DSB) repair, DNA-damage checkpoint function, and telomere maintenance, result in DSBs or exposed chromosomal ends. In the presence of p53, cells with DSBs or uncapped telomeres are predisposed to apoptosis, which limits tumorigenesis. If, however, p53 is absent, cells with DSBs or eroded telomeres can survive inappropriately, creating a permissive environment for the generation of genomic instability that can drive carcinogenesis. NHEJ, non-homologous end joining; HR, homologous recombination.
Why is apoptosis so popular?
Apoptosis has become one of the hottest areas of cell biology research, probably because of the belated realization that cell death is a biochemically regulated process that may be as complex as other fundamental biological processes.
What are the hypothesized phases of apoptosis?
Hypothesized phases in the induction of apoptosis in response to chemotherapeutic agents. In phase I, cytotoxic agents impart damage to a critical component of the cell such as DNA or microtubules. In phase II, the cell recognizes the damage and its degree of severity through poorly characterized signaling mechanisms.
What are the two major endogenous regulators of apoptosis?
In the 1980s, two major endogenous regulators of apoptosis were identified. Although initially identified as an oncoprotein, it soon became clear that the wild-type p53 protein functioned as an inducer of cell death, especially in response to DNA damaging events. 11-13 Reciprocally, studies on the Bcl-2 oncogene led to the identification of an important antiapoptotic function for this protein that therefore gave survival advantage to lymphomas that overexpressed the protein product. 14, 15 Bcl-2 is now appreciated to belong to a family of related and interacting molecules such as Bax, Bcl-x, Bad, Bag, Bak, and Bik, some of which are antiapoptotic, whereas other members of the family, such as Bax, display pro-apoptotic function. 15-17
Why is understanding the biochemical and molecular bases for this decision making by the cell (Fig 2) important?
Understanding the biochemical and molecular bases for this decision making by the cell (Fig 2) could allow a better therapeutic window to drive more cancer cells into apoptosis while preserving normal cells. This would result in better selectivity for cancer chemotherapy.
What is the treatment for cancer?
Over the last 3 to 5 decades, the treatment of cancer has relied primarily on the use of various forms of cytotoxic chemotherapy and radiation therapy . These interventions have had profound positive results on many hematologic malignancies and a few solid tumors, especially germ cell and some childhood malignancies.
What makes cancer cells resistant to chemotherapy?
(1) A cancer cell has a defect in one arm of induction of apoptosis, such as a mutation in p53, and the cell becomes resistant to activators of that arm (such as DNA-damaging agents).
What is the response to phase 3 cancer?
In many cancer cells, the preferred response is the induction of apoptosis, whereas in most normal cells and in many cancer cells, the response may involve growth arrest to allow for repair.
What is the therapy for apoptosis?
Therapies targeting apoptosis activate the proteins that promote apopto sis and block the activity of anti-apoptotic proteins. Targeted therapy for promoting apoptosis includes both small molecule drugs that can activate caspases inside the cell and monoclonal antibodies that activate receptors on the cell surface.
How is apoptosis regulated?
Apoptosis is strictly regulated by enzymes known as caspases which cleave the proteins in the cells when activated. Caspases are present in an inactive form in all cells, and when a caspase is activated, it triggers a cascade of downstream activity in all the caspases present in the cell. The caspases cleave all the proteins in the cell, ...
What is the function of BCL-2?
Bcl-2 are a family of apoptotic proteins that regulate the intracell apoptosis signaling. To activate the caspases and initiate apoptosis, the mitochondria (a cellular organelle that helps burn calories and other functions) releases a protein known as cytochrome c. Different proteins in the Bcl-2 family either suppress or promote the release of cytochrome c by altering the permeability of the mitochondrial membrane.
What are the different types of cancer drugs?
Two types of drug formulations are used in targeted cancer therapies: 1 Small molecule drugs: Minute particles that attach to proteins on the cell surface or get right inside the cell and modify its activity. 2 Monoclonal antibodies: Larger molecules that cannot get inside the cell, but attach to the cell surface and activate immune activity.
What is the IAP gene?
The inhibitor of apoptosis (IAP) family of genes encode proteins that suppress extracellular and intracellular signals and protect the cancer cell from apoptosis. A particular gene in the IAP family known as X-linked inhibitor of apoptosis (XIAP) is extremely potent in preventing apoptosis. Many cancers have a high presence ...
What are the defects in the cell signaling system that cause apoptosis?
Genetic mutations in the cancer cells lead to defects in cell-signaling systems that initiate apoptosis. The cancer cells hijack the family of proteins that regulate apoptosis, silence the pro-apoptosis proteins and overproduce the anti-apoptosis proteins.
Why do cancers start in cells?
Cancers most often start in a cell during cell division due to DNA damage or errors while copying (transcription) DNA. Genetic mutations are most often caused by hereditary factors, environmental factors and certain viral infections, but can sometimes happen for no fathomable reason.