Is NQO1 a suitable target for chemotherapy in Lung Cancer?

Introduction

Small Cell Lung Cancer (SCLC) represents about 13% of all lung cancer issues and continues to become a significant clinical health concern globally (American Cancer Society, 2019). The core reason for focusing on this type of cancer is based on the fact that it is a subtype of lung cancer that has no available effective treatment. Moreover, patients with the disease have a survival rate of about 16-24 months when exposed to chemotherapy and other concurrent thoracic radiations (Tsoukalas, et a. 2018 p. 145 & O’Brien, 2006 p. 5443). Under such conditions, it is crucial to understand its pathogenesis and whether NAD(P)H: quinone oxidoreductase 1 (NQO1) could emerge can be regarded as being the suitable target for chemotherapy in lung cancer.

Globally, the manufacture of effective and targeted diagnostic (theranostic) and therapeutic and chemotherapeutic agents is considered a highly accurate and dependable curative and diagnostic approach of lung cancer. As highlighted by Shin, Han, Verwilst, Kumar & Kim, (2016 p.  1419), NAD(P)H: quinone oxidoreductase 1 (NQO1) a common obligatory two-electron reductase that is reflected an excellent anti-cancer enzyme. In detail, NQO1 is an important cytosolic flavoenzyme that aid in the catalysis of the quinone 2-electron into simple hydroquinones that are then expelled out of the body. The human body cell has two core but, competing quinone metabolism pathways. In case one, quinones are passed through the one-electron reduction procedure that is catalyzed by enzymes such as P450 and b5 reductase. The outcome of the process is alkylating species and other free radicals. It is important to note that the metabolite semiquinone gets into an automatic oxidation process under the present aerobic conditions.  

In addition, NQO1 is thought to protect the cells from any unpredicted oxidative damage by blocking or barring quinones from infiltrating the one-electron reduction process. As a result, it results in less toxic hydroquinones that are readily excreted from the cells (Shin, Han, Verwilst, Kumar, & Kim, 2016 p.  1421). In vitro it has been proven that NQO1 have the potential of lowering the development of benzo(a)pyrene quinone-DNA that are produced by cytochrome P450 reductase. For that reason, NQO1 has been reflected as a dependable anti-cancer enzyme.  More evaluation by Begleiter, et al. (2009 p.3) showed that more levels of NAD(P)H:quinone oxidoreductase 1 were present in some lines of a variety of cancer cells when compared with other healthy cells. Resultantly, it has been depicted as an exceptional target for some of the drug delivery systems for cancer. With this understanding, this paper strives to explore whether NAD(P)H:quinone oxidoreductase 1 (NQO1) is indeed a suitable target for chemotherapy in lung cancer.

            During cancer therapy, the selective targeting of the cancerous cells as compared to other normal cells is its main goal. Unfortunately, some of the chemotherapeutics have been found to destroy rapidly dividing cell indiscriminately.  Despite the fact that some of these drugs can be effective in a certain environment, the inability to specifically target cancerous cells is the one which leads to dose limiting toxicities. Therefore, the best proven means of avoiding these toxicities entails targeting the aspects of the cancer a person has that cannot be shared with other normal cells (Ma, 2015 p.2)

            Although in normal cells its expression is quite low, it has been realized that it is greatly over-expressed in solid tumor including lung cancer (Guang-Zhi Dong, 2009 p.478). It is because of this over-expression that is regarded as being the main reason as to why NQO1 increases the progression of tumors.  Therefore, it implies that the NQO1’ over-expression as well as its association with the patient’s poor outcome is what equally makes it to be an intriguing agent (Kung, 2014 p.1). Although the inhibition activity of the NQO1 enzyme is regarded as being an anticancer strategy, it has never been successful.

Method

Epidemiologic studies examining the targeting NQO1 in lung cancer were obtained through searching the databases offered by ISI Web of Knowledge and PubMed database. The core keywords utilized in the search include ‘NQO1’, ‘NAD(P)H:quinone oxidoreductase 1’, ‘NAD(P)H:quinone oxidoreductase 1 targeting’, ‘’NQO1 targeting’, and ‘NQO1 target for chemotherapy in lung cancer.' The search gave about 21 articles with relevant keywords. However, to get the most updated information regarding NQO1 suitability as a the main target for lung cancer chemotherapy, all articles and journal older than five years were excluded from the study. From a total of 21 articles, the research was left with 11 articles. Another exclusion criterion included removal of all articles that were not written in English. After the exercise, four articles were removed leaving the study with seven articles. However, for accurate diagnostic and exploratory needs of lung cancer, the research reviewed the abstracts to all the seven articles to check the eligibility of their titles and the topic of study. The exercise cut off two articles from the study as they were more inclined towards other forms of cancer as opposed to lung cancer. In totality, five articles were left for study purposes.

Article Name		Keywords	Findings
1	Cancer Targeted Enzymatic Theranostic Prodrug: Precise Diagnosis and Chemotherapy.	’NQO1 targeting’, NAD(P)H:quinone oxidoreductase 1 NQO1 chemotherapy, NAD(P)H:quinone oxidoreductase 1	NQO1 is a suitable target for chemo prevents drugs. Furthermore, in order to manufacture other bio-reductive anticancer medicines, NQO1 is used for the purpose of activating such drugs so as to reduce its toxicity to cancerous cells.
2.	Roles of NAD (P) H-Quinone Oxidoreductase 1 (NQO1) On Cancer Progression and Chemoresistance.	NQO1 chemotherapy, NAD(P)H:quinone oxidoreductase 1	NQOI increases sensitivity of chemotherapy, therefore, a suitable target for chemotherapy in lung cancer. Additionally, the stabilization of human proteins using NQO1 occurs as a result of the inhibition of their degradation
3	Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents	NQO1 chemotherapy, NAD(P)H:quinone oxidoreductase 1	Inhibition of NQO1 could result in susceptibility of Cholangiocarcinoma (CCA) to different chemotherapeutic agents. The rate of oxygen consumption of the reactive oxygen species have the potential of causing dramatic DNA lesions that cannot be repaired easily.
4	Implications of NQO1 in cancer therapy	NQO1 chemotherapy, NAD(P)H:quinone oxidoreductase 1	NQO1 is a suitable therapeutic target for cancer related therapy. Taking into account its unique properties of moving its two-electron with the aid of either NADPH or NADH as reducing cofactors, NQO1 has the ability of catalyzing the exogenous and natural quinoneimines and quinones into toxic substance termed as hydroquinones.
5	Deoxynyboquinones as NQO1-Activated Cancer Therapeutics	NQO1, chemotherapy, NAD(P)H:quinone oxidoreductase 1	As a therapeutic target, NQO1-mediated activation works in killing cancer cells. Therefore, it a suitable target for chemotherapy
6	Nanotechnology-enabled delivery of NQO1 bioactivatable drugs’, Journal of Drug Targeting	Drug delivery, prodrug, NQO1, nanoparticles, b-lapachone, cabncer targeting	Considering its ability of inhibiting those processes, it is evident that NQO1 have the potential of reducing various substrates quinone-imines, quinones, and nitro compounds.
7	Quinone Reductases Multitasking in the Metabolic World’, Drug Metabolism Reviews	Antitumor quinone, quinone, DT-diaphorase, oxidative stress, NAD(P)H:quinone oxidoreductase, NQO1	The activity of NQO1 and its gene copy are always taken into consideration in the process of utilizing quinone molecules as the main drug against lung tumors
8	Anti-cancer effect of bio-reductive drug β-lapachon is enhanced by activating NQO1 with heat shock’, International Journal of Hyperthermia	Antitumor quinone, quinone, DT-diaphorase, oxidative stress, NAD(P)H:quinone oxidoreductase, NQO1	The reduction activity of the two-electron that are mainly catalyzed using NQO1 is perceived to be is beneficial to human cells through preventing the production of free radicals by the redox cycle.
9	Heat shock increases expression of NAD(P)H:quinone oxidoreductase (NQO1), mediator of β-lapachone cytotoxicity, by increasing NQO1 gene activity and via Hsp70-mediated stabilisation of NQO1 protein’, International Journal of Hyperthermia	Hsp70, Beta-lapachone, NQO1, hyperthemia	In some of the cancerous cells, for instance, non-small cell lung, the mechanisms of cell death is the one that switches its efficiency. Therefore, it is undoubtedly clear that NQO1 is indeed a dependable target zone for chemotherapy in lung cancer.

            A large number of the curative medicines that are used for the purpose of repairing end up failing because of the absence of tumor-selectivity. In the process of using β-lapachone and polymerase PARP inhibitors, it has been noted that the synergistic antitumor mainly evolves from unrelenting NAD (p) H levels that aid in refueling the recycling activity of the NQO1 (Guang-Zhi Dong, 2009 p.480). The synergistic antitumor effectiveness as well as the continued survival is the one that expands the use and effectiveness of the PARP inhibitors for the treatment of lung cancer in human (Lienhart, 2014 p.4692).

In summary, the values and arrangement of articles and journals reflect their ability to support the study question. The findings by each source are then compared with the results from the articles to ensure that accurate examination of whether NQO1 is a suitable target for lung cancer chemotherapy is achieved. It is crucial mentioning that the methodology showed that one sustainable way of preventing cancer development and spread is the suppression or clampdown of all carcinogenic metabolic activation processes. As a result, it works in preventing the production of the ultimate carcinogens. The findings and keywords as depicted in the above table show that NQO1 inhibits tumorigenesis in lung cells hence a good target for chemotherapy as it prevents carcinogenesis. 

Results

As revealed by the articles, NQO1 has biochemical roles that include protection, initiation, and promotion of cancer. Analytically, its roles could be categorized into four primary functions. They are detoxification of all quinone substrates through two-electron reduction, scavenging superoxide anion radicals, sustenance of endogenous antioxidants and finally stabilization of p33/p53/p73 proteins. While considering whether NQO1 is a suitable target for chemotherapy in lung cancer, it is crucial highlighting that its activities are easily up-regulated by dietary or chemical inducers. Consequently, having it as a suitable target for chemotherapy offers a dependable platform for lung cancer prevention.

In a normal environmental situation, exposure to quinones originate from the oxidizing metabolites of benzo(a)pyrene [benzo(a)pyrene 3,6-quinones] readily available in tobacco. As highlighted above, NQO1 catalyzes the single-step of two-electron reduction that works in reducing the quinones to hydroquinones. Hydroquinones are then conjugated and excreted from the body cells. In the specific process, NQO1 prevents the generation of free radicals throughout the redox cycle which means that it prevents the body cells from carcinogenesis. With the ability to inhibit such processes, NQO1 can reduce a wide range of substrates including quinone-imines, quinones, and nitro compounds present in events such as smoking. In totality, its performance and capacity to reduce carcinogenicity and toxicity of various quinones proves that it is a suitable target for chemotherapy in lung cancer cells. Reason being, it will help the chemo drugs to reach different quinones zones that have the potential to promote, initiate, or spread cancer cells in the lungs (Srijiwangsa & Na-Bangchang, 2017).

According to Oh & Park (2015), NQO1 has showcased the ability to scavenge superoxide available in NAD (P) dependent state. Structurally wise, vasculature cells where NQO1 is easily expressed are directly connected to the lungs. Therefore, the detoxification activity of NQO1 against superoxide anion radicals that are produced by cardiovascular tissues and NAD (P) H oxidases would help prevent the initiation and spread of cancer cells in the lungs. In totality, its detoxification ability reconfirms its capacity as an appropriate target for chemotherapy in lung cancer as it fits the toxins right from their source.

                                                            Discussion

            Furthermore, taking into account the targeted quinones, it is evident that the reduction of quinones by the NQO1-mediated 2-electron can either be one of the chemotherapeutic, detoxification or chemoprotection responses in the lung cancerous cells.  In the process of reducing toxic quinines using NQO1, such toxic substances end up being conjugated with glucuronic or glutathione acids before they are being excreted from the affected cells. Considering the protection the NQO1 provides, recent research indicates that the continued use of the dietary compounds for the purpose of reducing the expression of NQO1 is one of the successful means of preventing the development of lung cancer in human.

            Nevertheless, the reducing effect of the NQO1-mediated 2-electron is has the ability of converting compound of quinone to cytotoxic compounds hence resulting to cell death. Research indicates that the expression of NQO1 is large percent of human lung cancers is relatively high as compared to its expression in normal tissues. Therefore, this means that these tumors can be easily damaged using cytotoxic drugs relative to the normal tissues (Guang-Zhi Dong, 2009 p.479). It is important to review some of the biological role/roles of the NQO1 compounds in cancer and its potential curative target for lung cancer treatment.

            Despite the fact that the absence or the lowering of the activities of the NQO1 with the increased vulnerability of the development of cancer, medical research have proven that NQO1 is highly up-regulated in such cells. For the case of lung cancer chemotherapy, the increased expression of NQO1 has been noted to be highly connected with the late medical stage of differentiation (Lienhart, 2014 p.4694). The high expression of NQO1 in patients suffering from lung cancer, for instance, reveals low rates of disease free survival (DFS) as well as overall survival (OS) unlike in individuals with low NQO1 expressions. This implies that in lung cancer chemotherapy, the role played by NQO1 enzyme is relatively high as compared to the effect to induce in some of the adjacent normal tissues. 

            The modern medical research has proven that the reduction of quinones using NQO1 is one of its widely accepted and best described function. Ideally, environmental and endogenous quinones are some of the most reactive molecules that have the potential of reducing the development of cancer or its treatment. After reducing quinones into hydroquinones, it becomes easier for that compound to be removed from the body. As a result of that, it has been realized that the detoxification of the redox recycling of quinones using NQO1 also assist in protecting human cells from some of the oxidative stresses as well as preventing carcinogenesis.

            The reduction of menadione using NQO1 also has the ability of enhancing the formation of stable hydroquinone that can be easily conjugated as well as excreted from the human body in the process of treating lung cancer. Because of the number of times NQO1 is modified in transcriptomic and genomic level, the effect of its modulation on cancerous cells during chemotherapy places it as the main link connection between lung cancer redox resistance and alterations (Li, 2015 p.2). This means that one of the possible means of preventing the development of cancer entails suppressing the carcinogenic metabolic activations so as to prevent the production of carcinogens   (López, 2018 p.33).

            Likewise, studies have proven that the induction of these phase II enzyme mainly compares with the inhibition of the chemical mediated tumorigenesis and its promotion in the initiation stage. This implies that amongst all the phase II enzymes, it has been realized that NQO1 have the ability of inhibiting carcinogenesis.  Equally, when enhancing protection against the promotion as well as the development of lung cancer, the biochemical and the multiple roles of this enzyme can be categorized differently (Guang-Zhi Dong, 2009 p.478). The first category involves the use of its 2-electron reduction activity to boost the detoxification of the quinone molecules or substrates. The second one involves promoting the scavenging of the superoxide anion radicals (SOD).  The third role involves maintaining endogenous antioxidants for instance α-tocopherol and ubiquinone. The last role entails assisting in stabilizing suppressor proteins (Ross, 2004 p.643)

            Nevertheless, it has the realized that the use some of the chemopreventive agents to stimulate ARE/KEAP1/Nrf2 signaling pathway, resulting to the rise of its gene expression, has been perceived as being the main strategy of preventing lung cancer. For instance, during the bio-reduction of MMC using NQO1, it has been realized that the NQO1 levels is the one assists in predicting its sensitivity. Although other bio-reductive enzymes can be used in activating MMC, the polymorphism and expression levels of NQO1 aid in determining it medical response to MMC treatment.

Finally, tumor suppressor proteins such as p53 are well-known for their ability to suppress tumorigenesis by arresting growth as a response to DNA damage. According to Oh & Park (2015), p53 protein is regulated by modifying the interactions that affect its stability and half-life. Under normal conditions, p53 is gradually degraded as it interacts with chemicals or enzymes that induce proteasomal degradation. However, as discovered by Oh & Park (2015 p.14), NQO1 has proved its ability to stabilize the functions and ability of tumor suppressor protein (p53). It does that by inhibiting the proteasomal degradation process hence improving the performance of p53 thereby protecting the cell against carcinogenesis. Similarly, placing NQO1 as a target for chemotherapy in lung cancer would ensure that the drugs reach the specific cells without facing any inhabitation by enzymes in the body cells (Parkinson & Hergenrother, 2015).

Comparison of this research with previously published research

            Some of the accumulating evidence obtained from the previously published research regarding the adaptable cyto-protective roles of this substance particularly the prevention of lung cancer also proves how NQO1 is vital in treating cancerous cells. In addition to that, the role played by NQO1 polymorphism assists in explaining the generation of cancerous cells (Li, 2015 p.3). It should be noted that some of the compounds that are used also end up becoming cytotoxis because of the reduction activities that are accelerated by NQO1. In the process of damaging cancerous cells in lungs, previously published research suggests that it becomes easier to over-express NQO1 in those cells using some of the bio-reductive anticancer medicines (Benhamou, 2001 p.441). As a result of that, it is possible to induce the activities of NQO1 in cancerous cells for continues effectiveness of bio-reductive anticancer medicines.

Limitations

            Our research had various limitations. One of these limitations is that retrospective analysis of the effects of this enzyme on lung cancer chemotherapy was not properly done. The reason for that is because it was not possible to detect its curative effects. Another limitation is that although some of the p53 was highly assessed in exons 5-8, it was not easy to identify specific mutations using SSCP. As a result of that, the effect it induces on the expression of these proteins as well as its interactions with NQO1 is unknown. Furthermore, the findings of this research suggest that the study did not have the ability to utilize information from other multi-institutional trials. Finally, the data obtained from patients having various conditions that were linked with NQO1 polymorphism ended up weakening the results obtained from this research.

            During chemotherapy, the mechanisms of this enzyme, therefore, are the ones that aid in explaining the anti-tumor effects of these drugs. As compared with other previously published research, information obtained from Lap studies also suggest that the activated redox cycle of this enzyme does not have the ability of inducing a unique pathway for cell death, hence inhibiting the development of anti-tumor drugs (Song, 2008 p.162). The activation of NQO1 substrates after reduction is what makes them to be one of the promising strategies for enhancing lung cancer chemotherapy. Despite that, another publication bias discovered is that although NQO1 can be used to activate a number of the anti-tumor drugs, the truth is that they lack enough specificity and selectivity to NQO1.

Conclusion

The review has utilized five scholarly articles published in the last five years. From the analysis, it is evident that NQO1 has a vital role to play in reducing carcinogenesis. Moreover, the study has discovered that higher levels of NQO1 are available in cancerous cells as compared to normal cells. This then implies that it is an outstanding target which supports the creation and targeting of lung cancer chemotherapy drugs. The targeting is accurate and more focused on ensuring that carcinogenesis within the body cells is reduced. Following the above discoveries, it is essential concluding that, YES; NQO1 is a suitable target for lunch cancer chemotherapy.

            To enhance the treatment of cancer, some of compelling mechanisms of suicide substrates or NQO1 inhibitors have been developed. During lung cancer chemotherapy, the suggested mechanisms of cell death come as a result of the activation of the futile recycling of the anticancer drugs. In most cases, the death of the NQO1 expressing cells can also prevented using NQO1 inhibitors as well as cells having low resistance to NQO1 (López, 2018 p.30). For instance, to akylate the protein irreversibly, it becomes possible to inhibit the growth of cancerous cells in human hence suggesting its potential function for this compound as a curative agent.

             

 

 

 

 

 

 

 

 

 

 

 

 

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