Abstract
Cancer is a multifaceted disease, multiplies unmanageably and spread among the human body severely through the metastasis process. To address this challenging issue and to diminish progressive cancerous cells, high doses of radiation are implemented in radiotherapy. However, enormous cell death and potential impairment eventuated to tissues upon acute radiation exposure, resulting in the destruction of doublestranded DNA and inevitably death. Radioprotectors plays a pivotal role in the curation process of tumor in radiotherapy. In our opinion, due to the vital role of caspase-1 in the inflammatory immune response, it can serve as a function of a radioprotector. From a broader perspective, it may open a new window for researchers to discover novel therapeutic approaches to enhance human health. At the same time, it will be a crucial step to understand and unravel the controversial mechanism of action of caspase-1 and inflammation which may help to curb tumors with cancer patients in the near future.
Keywords: Radiation Therapy; Free Radicals; Radioprotectors; DNA; Caspase-1
Abbreviations: RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species; IR: Ionizing Radiation; FDA: Food and Drug Administration
Introduction
In the advancement of science, the employment of contemporary
radiation therapy (xRT); the most effective way to counter
malignancy, in the realm of cancer treatment has been exploited
in the last few decades extensively. Although, half of all cancer
patients worldwide, treated by radiotherapy may be responsible
for the consequential damage to healthy normal cells and acute
injuries to tissues which remains an enormous challenge to the
radiotherapist and oncologist [1]. On the other hand, tremendous
research which involves; novel drug development and innovative
strategies are in the phase of progress and is constantly evolving
across the globe to help reduce radiation-induced multiple sideeffects.
As massive doses of radiation are implemented as a part
of radiotherapy to cease the progress of cancerous cells, but at
the same time, it is harming enormously to the healthier normal
cells. The risk of damaging normal cells can be accomplished by
practicing an accurate and improved localization of radiation dose
and with the aid of several radioprotectors [2].
The most frequently applied techniques in anticancer treatment
include Ionizing radiation (IR), in particular X-rays and gamma-rays
owing to their huge potential to penetrate tissues; subsequently
rupture chemical bonds resulted in free electrons from atoms
which ionized, ultimately destroy the tumor cells. The water
molecules existent in the human organisms spontaneously (within
a few milliseconds) break down into active oxygen by radiation;
eventually, engender free radicals, Reactive Oxygen Species (ROS),
and Reactive Nitrogen Species (RNS) [3], which subsequently
impair cells and in extreme cases leads to death. The generated
free radicals’ interplay with DNA, RNA, proteins and resulted in
cell dysfunction and further fatality. Also, these active free radicals
induce oxidative stress among healthy organisms in physiological and pathological processes, which is one of the causative factors for
tumors, hence, therefore, further exploration and the investigation
of a powerful free radical scavenger is urgently needed.
The fundamental goal of radiotherapy is to help destroy
cancerous cells specifically without or negligible harm to the normal
healthier cells and tissues. This process can be accomplished either
by irradiation at tumor cells particularly or by employing various
radioprotecting agents to minimize the risk [4]. The one of the best
key model to downplay the risk of damaging cells is to eradicate
free radicals which produced in due course of radiotherapy from
the human body. In the broader sense, primarily it causes DNA
double-strand rupture during irradiation. Many researchers
around the world are thus, formulating diverse radiosensitizing
agents and radioprotectors as a protective agent that can shield the
human body in radiotherapy to curb adverse effects. In our opinion
caspase-1, an eminent inhibitor that interplays a critical role in
radiation-induced apoptosis can become an additional option as a
radioprotector and will open new windows of opportunities in the
application domain of radiotherapy.
Radioprotectors
Radioprotectors are compounds that are introduced before or
at the time of radiation to diminish impairment occurred during
acute radiation exposure in the treatment against cancer. At the
same time, radioprotectors, facilitate to restraint of the worsening
of normal healthy cells in the process of radiotherapy in many
regards. To date, Amifostine (WR-2721) which is the only U.S.
Food and Drug Administration (FDA) permitted radioprotector;
mechanistically scavenges the highly reactive free radicals
generated by ionizing radiation in radiotherapy. However, only a
high concentration dose is beneficial in radiotherapy which also
decayed within 30 minutes. Additionally, it may cause adverse sidereactions
for example vomiting, nausea, diarrhea, neurotoxicity,
sneezing, and, dizziness, etc. [5]. Nitroxides, the most promising
future radioprotector capable to detoxify ROS; still under the
pathway of clinical trials. Other antioxidants, the naturally occurring
radioprotectors, including glutathione, lipoic acid, vitamins A, C,
and E have less efficacy and non-selective free radical scavenging
ability in comparison with the synthetic agents.
Their mode of action includes detoxification of ROS, tyrosine
kinase inhibitor and, hematopoietic stem cell quiescence.
Superoxide dismutase (SOD), an enzyme that naturally exists in
human cells; which catalyzes and detoxifies the highly reactive
superoxide to oxygen (O2) and hydrogen peroxide(H2O2), free
radicals generated upon radiation exposure [6]. Furthermore,
Cytokines and growth factors also play a role of radioprotector,
serve to stimulates proliferation and differentiation, DNA repair and
ROS detoxification. ACE inhibitors operate through the mechanism
of angiotensin II inhibition, suppression of radiation-induced
proliferation, NOS synthesis and, TGF-β induction. In addition,
many other nano-particle-based, novel radioprotectors are in the
progressive stages with a diverse application, mode of action, and
their relevant side effects. The aforementioned limitations impart
massive challenges in front of researchers to discover effective
radioprotectors.
Caspase-1
The neuronal cell death emerges via two main pathwaysextrinsic
(death receptors) and intrinsic (mitochondria). Among
these, the caspase follows the mitochondrial pathway after exposure
to acute radiation. The caspases, conduct a pivotal role in complex
physiopathological processes to regulate apoptosis and which
also contribute to inhibiting radiation-induced apoptosis [7]. The
intracellular cysteine proteases family includes the inflammasomes
caspases which are solemnly responsible to split an insignificant
number of substrates exhibits succeeding aspartic acid residues
[8]. To date, extensive research has been performed to understand
the significant role of caspases in the complex biological process
of apoptosis. This caspases family is mainly categorized into
inflammatory mediated caspases (caspase-1, 4, 5, 11, and 12) and
apoptotic (caspase-2, 3, 6, 7, 8, 9, and 10). Amid diverse caspase
families, inclusive of human caspase-1, caspase-4, and caspase-5
and other mouse caspase-1, caspase-11, and caspase-12, are
well-known ‘proinflammatory caspases’ as specifically, they are
frequently participating in the biological processes and secretion of
proinflammatory molecules.
Among those, Caspase-1 is first discovered in 1989 and then
consistently studied and well-characterized in 1992 [9,10]. As one
of the most significant and systematically investigated caspase-
1(inflammatory mediated) which triggers the inflammatory
response process via the stimulation of pro-inflammatory
cytokines, in particular, interleukin-1β (IL-1β) and IL- 18 as well as
the pyroptosis [11]. After maturation, the cytokines subsequently
start signaling events to stimulate a pro-inflammatory response; its
corresponding swiftness, selectivity, and sort of reply are subject to
the signal received together with the sensor protein which receives
signals. Thus, an activated Caspase-1 can provoke pyroptosis (a
lytic form of cell death) reliant on the signal received. However
inflammatory response can occur with or without pyroptosis,
but prior pyroptosis process, the inflammatory response is fully
necessary [12].
However, the precise mechanisms underlying this pathology
remain unraveled. It is renowned fact that inflammation is an
important pathway in the host defense system. Inflammasomes are
associated with acute danger or pathogen-related inflammation;
besides, they engaged in the growth of inflammation-induced illnesses, for instance, cancer and many others. Pyroptosis which
is a lytic form of programmed cell death is mainly governed by
caspase-1 and triggers IL-1- or IL-18 related inflammatory response.
Regulating diverse and moderately opposing pathways, caspase-1
assist innate and adaptive immunologic defense mechanisms.
Experimentally, it was proven that caspase-1 helps cell survival
by activating NF-kB, triggers membrane repair, and controls the
eccentric discharge of certain proteins [13]. As undesirable adverse
effects occur during the course of radiation therapy, which also
involves cell and tissue damages.
Considering the aforementioned facts in mind, in our viewpoint,
owing to its central role in the inflammatory immune response,
caspase-1 which triggers the inflammatory response by activation;
may play a promising role in the inflammation that occurs during
radiation. Thus, caspase-1 may become a new therapeutic target for
irradiation in cancer treatment. In this regard, critical mechanisms
of inflammatory caspase-1 and its radioprotecting ability have to be
investigated in detail.
Conclusion
This review summarizes the interplay of radiation and its critical role in the curation of tumors and how it damaging healthier normal cells in conjugation with cancerous cells by generating active free radicals which eventually facilitate impairment and rupturing the DNA double-strand which ultimate results in mortality. Further, radiosensitizing agents and radioprotectors are the better alternative options to beat tumor, however, due to their own limitations, novel methodologies has more scope. It is, therefore, a crucial challenge to unravel and to procure a deep understanding of the critical mechanisms of inflammatory caspase-1 and its radioprotecting ability in front of researchers; it may open new doors in the field of radiotherapy to engender novel therapeutic strategies for ameliorating human health in the forthcoming future to the cancerous patient.
Acknowledgment
This work was supported by the National Research Foundation of Korea (NRF) Grants (NRF-2017M3A9E4077205).
Conflict of Interest
The authors declare no conflict of interest, financial or otherwise.
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