Fall Semester2022-2023

Apoptosis and Cancer

Introduction:

Apoptosis, which is the programed cell death, is typically characterized with several
morphological features and energy-dependent molecular pathways. It is also known as an
essential part of many different processes including healthy cell turnover, immune system
development and function, hormone-dependent atrophy, embryonic development, and
chemically induced cell death. Inappropriate balance in apoptosis can lead to uncontrolled
problems and diseases in human such as neurological diseases, autoimmune disorders,
various types of cancer and damage by ischemia. This could be caused by many distinct
factors including a DNA mutation amplifying by constant cell divisions resulting in no
apoptosis of the growing mutated cells and thus carcinogenesis. Therefore, the therapeutic
potential of controlling a cell’s ability to stay alive or die is of great importance and has
recently been the main subject on the table for researchers in order to find the most efficient
way of treating cancer by majorly examining cell cycle and signalling pathways that regulate
the cell death.
The Framework of Apoptosis:
Apoptosis is detected by its morphological aspects such as cell shrinkage, membrane
blebbing, chromatin condensation, and nuclear disintegration. However, the proven theory
of apoptosis being a gene-directed program has implanted even more theories and questions
concerning developmental biology and tissue homeostasis, to eventually deducing that cell
numbers can be influenced by factors which influence cell survival as well as those that
control proliferation and differentiation. Furthermore, the genetic foundation of apoptosis
suggests that mutations can impair cell death, just like they can impair any other metabolic
or developmental program. In fact, it has been currently stated and proven that any mistake
occurring in any of the apoptotic pathways will have a role in many human diseases,
including cancer mainly and neurological disorders.
Evasion of Cancer:
Apoptosis and the malignant phenotype have been linked since the early 1970s, according to
some theories. In fact, observed tumor growth rates may be only 5% of what would be
expected from proliferative data alone, according to kinetic studies of tumor growth.
Changes in this "cell loss factor" could, in theory, have a significant effect on the
development or progression of tumors. Kerr et al. suggested the notion that a significant
portion of cell loss from tumors was caused by apoptosis, even though the majority of this
mortality was thought to be from necrosis—a catastrophic (and obvious) type of cell death.
According to some studies, apoptosis and the malignant phenotype are related since the early
1970s. In fact, observed tumor growth rates may be only 5% of what would be expected
from proliferative data alone, according to kinetic studies of tumor growth. Changes in this
"cell loss factor" could, in theory, have a significant effect on the development or
progression of tumors. Kerr et al. proposed that a considerable part of cell loss from tumors
was caused by apoptosis, in spite that necrosis—a catastrophic (and visible) type of cell
death—was assumed to account for most of this mortality. In tumors that were treated with
cytotoxic anticancer drugs as well as tumors that were naturally regressing, subsequent
studies found a significant frequency of apoptosis.
Pro- and anti-apoptotic members of the Bcl-2 protein family play a crucial role in the control
of apoptosis, particularly via the intrinsic route as they are found upstream of irreversible
cellular damage and primarily function at the mitochondrial level. BCL2, the second
member of a group of proteins present in human B-cell lymphomas with the t (14; 18)
chromosomal translocation, is encoded by the BCL2 gene. Bcl-2 was the first protein of this
family to be identified more than 20 years ago.

Pro-apoptotic and apoptotic inhibitors:

All Bcl-2 members are found in the outer mitochondrial membrane. They are dimmers, and
they are in charge of pore or ion channel formation, which causes membrane permeability.
Bcl-2 family members are further classified into three groups based on their function and
BH domains. The first category includes anti-apoptotic proteins, which contain all four BH
domains and protect against apoptotic stimuli. Examples include Bcl-2, Bcl-xL, Mcl-1, Bcl-
w, A1/Bfl-1, and Bcl-B/Bcl2L10. The second category consists of BH-3 only proteins, so
named because they are limited to the BH3 domain in comparison to the other members.
This category includes the names Bid, Bim, Puma, Noxa, Bad, Bmf, Hrk, and Bik. The
BH3-only proteins, which are apoptosis initiators, are activated during times of cellular
stress such as DNA damage, a lack of growth factors, and endoplasmic reticulum stress. As
a result, they favor apoptosis. Members of the third group are pro-apoptotic and have all four
BH domains. Bax, Bak, and Bok/Mtd are a few examples.

Apoptotic Failure:

Apoptotic evasion by cancer is induced when there is an imbalance in the Bcl-2 family.
Some anti-apoptotic proteins may be overexpressed while some pro-apoptotic proteins may
be under expressed. When the delicate balance of anti- and pro-apoptotic members in the
Bcl-2 family is upset, apoptosis upregulation occurs in the affected cells. Anti-apoptotic
proteins may be over-expressed, pro-apoptotic proteins may be under-expressed, or both
may be detectable. Over-expression of Bcl-2, for example, inhibited TRAIL-induced
apoptosis in neuroblastoma, glioblastoma, and breast carcinoma cells [37], while Raffo et al
demonstrated that Bcl-2 over-expression protected prostate cancer cells from apoptosis.
Furthermore, over-expression of Bcl-xL causes tumor cells to exhibit a multi-drug resistance
phenotype and prevents them from undergoing apoptosis. The bax gene is mutated
frequently in colorectal tumors that have micro satellite instability, on the other hand.
Bax(G)8 frameshift mutations have been shown by Miquel et al to affect apoptosis, which
can make colorectal cancer cells resistant to anticancer therapies. With high amounts of the
anti-apoptotic protein Bcl-2 and low levels of the pro-apoptotic protein Bax in vivo,
malignant cells in chronic lymphocytic leukemia (CLL) exhibit an anti-apoptotic phenotype.
In vivo, leukemogenesis in CLL is caused by decreased apoptosis as opposed to enhanced
proliferation. According to Pepper et al., drug-induced apoptosis in B-CLL cells was
inversely correlated with Bcl-2/Bax ratios when these cells were grown in vitro. B-
lymphocytes in CLL exhibited an increased Bcl-2/Bax ratio in individuals with CLL.
Another way that apoptosis is evaded is through the p53 tumor suppressor protein. It is one
of the most well-known proteins that have a role in apoptosis. It is known as the "guardian
of the genome" because in addition to playing a crucial role in regulating the cell cycle,
development, differentiation, gene amplification, DNA recombination, chromosomal
segregation, and cellular senescence. It was first discovered in 1979 as a cellular protein
accumulating in the nuclei of cancer cells and a transformation-related protein that strongly
bound to the big T antigen of the simian virus 40 (SV40). It was initially determined to be
barely carcinogenic, however, now than 50% of human malignancies have been linked to
defects in the p53 tumor suppressor gene. Avery-Kieida et al. recently reported that some of
p53's target genes involved in regulating apoptosis and the cell cycle are abnormally
expressed in melanoma cells, resulting in abnormal p53 activity, and promoting the growth
of these cells. Additionally, it was discovered that silencing the p53 mutant caused mutant
p53 expression to be down regulated, which in turn reduced the growth of cellular colonies
in human cancer cells. Further developments revealed that its mutation plays a key role in
inducing oncogenic features. It was later referred to as a “gain of oncogenic function”.

Treatment Pathways and Drugs:

One important mechanism by which cytotoxic medicines destroy tumor cells is the
activation of apoptotic pathways. Apoptosis-sensitive target cells are important for
immunotherapy of malignancies. The deficiencies in apoptotic signaling cause tumor
resistance. It was observed that after the treatment with a cytotoxic medicine activates the
apoptotic signaling demonstrating the mitochondrial pathway, in other words the intrinsic
pathway in which cytochrome C is released triggering apoptosis. Moreover, the
susceptibility of the tumor cells to the cytotoxic therapy is influenced by the death receptor
which activates the extrinsic apoptotic pathway.

When caspases which are the molecules responsible for most cell deaths, as mentioned
above, are activated, both the extrinsic and intrinsic pathways come together.
Apoptotic resistance can be overcome by various mechanisms, including: direct targeting of
anti-apoptotic molecules expressed in tumors, re-expression of caspases in previously
resistant tumor cells, anti-apoptotic molecules such as Bcl-2 and molecules of his IAP
family of endogenous caspase inhibitors. antagonize. Future therapeutic strategies will
benefit from novel targets for logical therapeutic intervention arising from molecular
insights into the regulation of apoptosis and defects in apoptotic signaling in tumor cells.

Defects and abnormalities along apoptotic pathways can be valuable targets for cancer
therapy, which is a double-edged sword. Cancer cells that depend on these abnormalities for
survival can be disrupted by drugs or therapeutic approaches that can normalize apoptotic
signaling pathways. A number of important recent discoveries have opened new doors to
potential new classes of anticancer agents. Inhibiting the Bcl-2 family of anti-apoptotic
proteins using therapeutic agents or silencing the elevated anti-apoptotic proteins or genes
involved are some of the possible ways to target proteins of the Bcl-2 family. It's a cure.
His one good example of these drugs, oblimersen sodium, a Bcl-2 antisense oligomer and
his first Bcl-2 drug to enter clinical trials. The chemosensitizing effect of this drug has been
observed to improve survival in chronic myelogenous leukemia patients administered in
combination with conventional anticancer agents. Small molecule inhibitors of the Bcl-2
family of proteins are further examples of this group. These can also be broken down into
her two categories: compounds that affect gene or protein expression and molecules that act
directly on proteins. Examples of the first category include gossypol, sodium butyrate,
depsipeptide, fenretinide, and flavopiridol.

Some of these small compounds are part of another class of drugs known as BH3 mimetics,
which mimic the way only BH3 proteins bind to the hydrophobic groove of anti-apoptotic
Bcl-2 family proteins, hence their was named as ABT-737, which inhibits anti-apoptotic
proteins such as Bcl-2, Bcl-xL and Bcl-W, is a well-known example of a BH3 mimetic. In
highly curative animal models, it has been shown to be cytotoxic in lymphoma, small cell
lung cancer cell lines, and primary patient-derived cells, causing regression of established
tumors. Mcl-1 has been reported to bind and inhibit other BH3 mimics such as ATF4, ATF3
and NOXA. Many p53-based cancer therapies are being investigated. Most of these, fall into
one of three general categories: gene therapy, pharmacological therapy, or immunotherapy.
The first publications on p53 gene therapy involved the use of retroviral vectors containing
the wild-type p53 gene injected into patient-derived tumor cells. The first publications on
p53 gene therapy involved the use of retroviral vectors containing the wild-type p53 gene
injected into patient-derived tumor cells. Subsequent studies explored combining p53 gene
therapy with additional anticancer tactics, as using the p53 gene alone was insufficient to
eliminate all tumor cells. For example, insertion of the wild type p53 gene has been shown
to make head and neck, colon, prostate and glioma tumor cells more sensitive to ionizing
radiation. Some of the studies have moved into Phase III clinical trials, but the FDA has not
yet granted final approval. Elimination of p53-deficient cells with custom-made viruses is an
interesting p53 gene-based strategy. One such case is the use of the recombinant oncolytic
adenovirus ONYX-015. In this virus, the E1B 55 kDa gene has been deleted, allowing the
virus to preferentially replicate and lyse p53-deficient tumor cells.
Several drugs have been developed that artificially activate caspases. For example, apoptin,
a caspase inducer originally derived from chicken anemia virus, selectively induced
apoptosis in malignant but not healthy cells. Small-molecule caspase activators are another
family of drugs that activate caspases. These peptides have an arginine-glycine-aspartate
pattern. They can directly trigger the autoactivation of procaspase-3 and are pro-apoptotic.
They have also been shown to lower the threshold for caspase activation or activate
caspases. This makes the cancer cells more sensitive to the drug.

Conclusion:

The tremendous sum of theories focusses on the significance of apoptotic pathway

anomalies in carcinogenesis as well as the viability and potential of various inventive
apoptosis-targeting therapeutic approaches for the treatment of different cancers. These
discoveries run from preclinical to those that have already begun clinical trials. Various
clinical trials including conventional anticancer drugs have also included a number of these
new compounds or treatment strategies, which may improve now available treatment
alternatives. A few puzzling and unsettling questions, in any case, such as whether these
therapeutic approaches empower tumors to become safe to them and whether they would
result in the mass passing of typical cells, stay uncertain. If conventional anticancer
medications are any sign, this is a genuine stress since they kill both typical and tumor cells
whereas causing severe side effects and tumor resistance. However, if these compounds that
target apoptosis are selectively working on a single pathway or protein, that would be
advantageous clinically. Although several inhibitors of the Bcl-family of proteins and some
pan-IAP inhibitors are among the compounds that enter clinical trials, the majority of them
act on multiple targets. Therefore, evidence-based long-term follow-ups on patients
receiving these new cancer treatments are required, and continued research should
concentrate on those methods that can specifically cause apoptosis in cancer cells rather than
normal cells.

Hiba Khaled Al Kurdi

ID: 202100288