Dear Editor,
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Globally, the coronavirus disease‐2019 (COVID‐19) pandemic has spread rapidly, with
millions of confirmed cases. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2),
is responsible for this disease (Etemadifar et al., 2021; Zalpoor et al., 2022). Based
on the studies, it seems that cancer patients not only are more prone to experience
severe complications and death by COVID‐19 (Y. Tian et al., 2021) but also cancer
progression by COVID‐19 (Purcaru et al., 2021).
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COVID‐19 AND ACTIVATION OF mTOR AND HIF‐1α
The activity of SARS‐CoV‐2 in human organs and the immune system can lead to the activation
of some crucial signaling pathways. For instance, in infected cells, SARS‐CoV‐2 stimulates
the mammalian target of the rapamycin (mTOR) signaling pathway in order to facilitate
the transcription of viral structural proteins. On the other hand, according to Ramaiah's
hypothesis, the nonstructural protein of SARS‐CoV‐2 in human cells causes the stability
of E3 ubiquitin (E3U) ligase ring‐finger and CHY zinc‐finger domain‐containing 1 (RCHY1)
leading to P53 degradation. P53 is involved in the transcription of some miRNAs that
result in posttranscriptional mTOR gene silencing. Hence, the degradation of P53 is
in favor of mTOR signaling pathway (Ramaiah, 2020). After infection, damage‐associated
molecular patterns (DAMPs) are released from infected cells and bind to toll‐like
receptors (TLRs) on immune cells, such as dendritic cells (DCs), and activate.
PI3K/Akt/mTOR signaling pathway. Activation of this signaling pathway leads to the
release of high levels of inflammatory cytokines (Omarjee et al., 2020). Many types
of cancer exhibit aberrant mTOR signaling due to genetic alterations at various levels
of the signal cascade. It reveals that mTOR exerts a significant role in cancer progression
and in the increase of cell metabolism, cell growth, cell survival, and protein synthesis
following upstream signals in cancer (T. Tian, Li, & Zhang, 2019).
Hypoxia‐inducible factor‐1α (HIF‐1α) as a transcription factor is activated in hypoxic
conditions. Increasing HIF‐1α during SARS‐CoV‐2 infection increases a disintegrin
and metalloprotease 17 (ADAM17) expression. This factor increases the inflammation
and processes TNF‐α and increases absorption of processed TNF‐α by innate immune cells.
ADAM17 also cleavages the IL‐6/IL‐6R/gp130 and converts IL‐6R into a pro‐inflammatory
factor leading to a cytokine storm (Serebrovska, Chong, Serebrovska, Tumanovska, &
Xi, 2020). In addition, HIF‐1α transcriptional activity can alter genes expression
related to cancer progression, autophagy, which can lead to drug resistance, immune‐suppression,
glucose consumption and metabolic pathways, cell proliferation, angiogenesis, and
metastasis (Rashid et al., 2021).
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QUERCETIN ANTI‐COVID‐19 EFFECTS
Quercetin is the major polyphenolic flavonoid that can be naturally received through
various fruits and vegetables, including apples, onions, berries, capers, lovage,
dill, and cilantro or artificially from supplementary tablets containing quercetin
or its synthetic derivatives. Quercetin exhibits significant antiviral, pro‐metabolic,
and antiinflammatory properties. Recent studies have been suggested that quercetin
potentially can exert its role as anti‐COVID‐19 agent through multiple mechanisms;
(a) disrupting the interaction of SARS‐CoV‐2S protein with its specific receptor ACE2,
which can prevent the viral entry to the host cells; it was reported that quercetin
tightly bound to S protein with a—7.8 kcal/mol binding affinity at its Gly496, Asn501,
Tyr505, and Tyr453 residues. (b) Interfering with SARS‐CoV‐2 replication. Nguyen et
al. and Ryu et al. have revealed that quercetin has inhibitory activity against 3C‐like
protease (3CLpro), as a vital for the replication of SARS‐CoV, with an IC50 of 73 μM.
Moreover, it was proved that quercetin has strong interaction with SARS‐CoV‐2 Mpro,
as a protease facilitating the virus RNA translation (Derosa, Maffioli, D'Angelo,
& Di Pierro, 2021; Nguyen et al., 2012; Ryu et al., 2010; Vijayakumar, Ramesh, Joji,
& Kannan, 2020). (c) Reducing the cytokine storm with its antiinflammatory response
(Derosa et al., 2021). As a result of adding quercetin to cultured peripheral mononuclear
cells, it induces the production of (Th‐1)‐derived Interferon‐α (IFN‐α) and lowers
the production of the Th2‐derived IL‐4 (Tanaka, Furuta, Asano, & Kobayashi, 2020).
TABLE 1
Anticancer effects of quercetin
Pathway–factor
Cancer
Mechanism–function
References
PI3K/Akt/mTOR
Colon cancer
Upregulation of the endocannabinoid receptor (CB1R) and PI3K/Akt/mTOR modulation
Refolo et al. (2015)
Colon cancer cell lines
Apoptosis induction via sestrin induction of 2/AMPK/mTOR pathway and increasing intracellular
ROS in cancer cells
Kim et al. (2013)
U937 human leukemia cells
Suppresses cell proliferation and promotes death by reducing the Bcl2‐to‐Bax ratio
Rauf et al. (2018)
EBV‐negative Burkitt's lymphoma cells
Attenuating c‐Myc expression and inhibition of PI3K/Akt/mTOR activity
Granato et al. (2016)
Glioblastoma multiforme (GBM)
Interacting with signal transduction pathways, including PI3K/Akt/mTOR and its downstream
proteins playing role in GBM cell growth
Tavana et al. (2020)
P388 leukemic cells, and U937 human leukemia cells
Decrease 2Notch 1 expression and phosphorylation of its downstream signaling proteins
Akt and mTOR
Rauf et al. (2018)
HIF‐1α and VEGF
Human prostate cancer LNCaP, colon cancer CX‐1, and breast cancer SkBr3 cell lines
Downregulating the angiogenesis factors of HIF‐1α and VEGF
Rauf et al. (2018); Refolo et al. (2015)
Two interventional clinical trials (ClinicalTrial. gov identifiers: NCT04377789 and
NCT04468139) suggested a daily dose of 1,000 mg quercetin alone and its 500 mg concomitant
use with zinc, bromelain, and vitamin C in COVID‐19 patients, respectively. In addition,
another study on 152 COVID‐19 patients, indicated that 1,000 mg of quercetin for 30 days
significantly reduced length of hospitalization, in need of noninvasive oxygen therapy,
in progression to intensive care units, and in number of deaths (Di Pierro et al., 2021).
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QUERCETIN ANTICANCER EFFECTS
Quercetin has been demonstrated to have anticancer properties in numerous in vitro
and in vivo studies with various cell lines and animal models. Quercetin inhibits
the spread of malignancies such as lung, prostate, liver, breast, colon, pancreatic,
bladder, gastric, bone, blood, brain, head and neck, skin, eye, thyroid, ovarian,
kidney, mesothelioma, and cervical cancers. However, quercetin appears to be free
of side effects or harm to normal cells, despite its high toxicity to cancer cells.
Various mechanisms can exert these anticancer properties, including the cellular signaling
pathway and the ability to inhibit enzymes that activate carcinogens (Rauf et al., 2018)
(Table
1
). Refolo et al. have shown that quercetin increases the expression of the endocannabinoid
receptor (CB1R) and reduces PI3K/Akt/mTOR in human colon cancer cells (Refolo et al., 2015).
Moreover, other researchers found that the quercetin‐induced apoptosis involves the
sestrin 2/AMPK/mTOR pathway by regulating increased intracellular ROS in colon cancer
cell lines (Kim, Lee, & Kim, 2013). Quercetin suppresses cell proliferation and promotes
death in U937 human leukemia cells via reducing the Bcl2‐to‐Bax ratio. It significantly
reduces tumor cell penetration as well as the expression of angiogenesis‐related proteins
HIF‐1 and VEGF. The expression of 2Notch 1 and the phosphorylation stages of the downstream
signaling proteins Akt and mTOR are significantly lowered by quercetin (Rauf et al., 2018).
In addition, Granato et al. have shown that quercetin decreases c‐Myc expression and
inhibits PI3K/Akt/mTOR activity in EBV‐negative Burkitt's lymphoma cells (Granato
et al., 2016). The researchers further suggested quercetin might be used as a treatment
for glioblastoma multiforme (GBM). In terms of molecular interactions, quercetin has
been found to interact with proteins involved in GBM cell growth and signal transduction
pathways, including PI3K/Akt/mTOR (Tavana et al., 2020).
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QUERCETIN POTENTIAL EFFECTS IN INHIBITION OF mTOR AND HIF‐1α
Quercetin, as a flavonol with antiinflammatory and antioxidant properties, promisingly
exerts antitumor roles by regulating a variety of cancer signaling pathways, affecting
the activity of mTOR and HIF‐1 in particular (Bruning, 2013; Samec et al., 2021) (Figure 1).
It has been demonstrated that quercetin inhibits the mTOR signaling pathway and that
it also interferes with AMP‐dependent protein kinase (AMPK) activity, PI3K‐dependent
Akt stimulation, and hamartin upregulation. As a dual‐specific mTOR/PI3K inhibitor,
quercetin is able to suppress both mTOR activity and PI3K activation. Cell growth,
protein biosynthesis, and autophagy are crucial processes controlled by the mTOR complex,
which is often hyperactive in cancer (Bruning, 2013). It has been reported that quercetin
inhibits the accumulation of HIF‐1α, in addition to HIF‐1α protein expression during
hypoxic conditions in various cancer cell lines, such as SkBr3 breast cancer cells,
LNCaP prostate cancer cells, and CX‐1 colon cancer cells (18). Surprisingly, it has
been reported that quercetin has the same effect on HIF‐1α expression as cycloheximide
(a HIF‐1α inhibitor drug) (Lee & Lee, 2008).
FIGURE 1
Quercetin potential effects against SARS‐CoV‐2 infection and COVID‐19‐associated cancer
progression by inhibiting mTOR and hypoxia‐inducible factor‐1α (HIF‐1α). COVID‐19,
coronavirus disease‐2019; mTOR, mammalian target of rapamycin; SARS‐CoV‐2, severe
acute respiratory syndrome Coronavirus 2
Consequently, the potential of quercetin in inhibiting mTOR and HIF‐1α activity and
expression by multiple pathways is the reason that this bioflavonoid is an attractive
therapeutic candidate for various cancers and other diseases involved with mTOR activity.
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CONCLUSION
Due to the susceptibility of cancer patients to COVID‐19, we suggested that using
drugs with few or no adverse effects that have therapeutic effects against COVID‐19
and cancer could be very beneficial. We hypothesize that quercetin, as a safe flavonoid
that exists in various fruits and vegetables, not only can be used as an anti‐COVID‐19
component with potential effects on interfacing the viral entry, replication, and
its inflammatory activity but also can disrupt the signaling pathways stimulated and
upregulated factors by SARS‐CoV‐2 infection (e.g., mTOR, HIF‐1α, etc.), which may
lead to cancer progression. Thus, quercetin therapy may be a potential strategy to
decrease SARS‐CoV‐2 infection and improve its desirable effects particularly, in susceptible
cancerous patients with severe complications or who passed their chemotherapy–radiotherapy
period. We hope that this study will draw more attention to the use of quercetin in
clinical research and treatments for COVID‐19 patients, especially cancer patients
with COVID‐19 infection.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
Hamidreza Zalpoor: Study design and concept; writing‐original draft; manuscript revision.
Maryam Bakhtiyari: Writing‐original draft; figure creation; manuscript revision. Mahsa
Liaghat: Writing‐original draft. Mohsen Nabi‐Afjadi: Writing‐original draft; manuscript
revision. Mazdak Ganjalikhani‐Hakemi: Study Supervision. All authors read and approved
the final manuscript.