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
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 . 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 .
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) , 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 . 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 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. . 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 . 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.
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 . 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
. 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
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 . 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 .
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 . 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.
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.
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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