Volume 8, Issue 2 (2022)                   Pharm Biomed Res 2022, 8(2): 91-94 | Back to browse issues page


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Pashmforosh M, Shariati S, Aghaei Nezhad H, Haghighat M. Possible Benefits of Paclitaxel Therapy for COVID-19. Pharm Biomed Res 2022; 8 (2) :91-94
URL: http://pbr.mazums.ac.ir/article-1-420-en.html
1- Department of Basic Sciences, Faculty of Medical Sciences, Behbahan University of Medical Sciences, Behbahan, Iran.
2- Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Dear Editor
The coronavirus disease 2019 (COVID-19) was reported in Wuhan, China, in late December 2019 and soon became the most serious global health challenge due to the high rate of human-to-human transmission. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus and belongs to the large Coronaviridae family [1]. The pathogenesis of the COVID-19 still remains poorly understood. Cytokine storm, a hyper-inflammatory state, is considered one of the most important causes of respiratory distress syndrome (ARDS) and death in patients with COVID-19. Clinical studies have reported that there is a strong association between the level of inflammatory cytokines and the severity of the COVID-19 [2]. The prognosis of the COVID-19 is good in most patients; however, in a small number of patients, it develops into ARDS and subsequently, death within a short time [1]. Given that there is no specific antiviral drug for the treatment of the disease, suppression of cytokine storms using FDA-approved drugs with multiple mechanisms of action may reduce the COVID-19-related mortality.
Paclitaxel, an antineoplastic drug extracted from the Taxus brevifolia tree, is used to treat ovarian and breast cancer. It stabilizes microtubule polymer and prevents the disassembly of microtubules leading to inhibition of cell division [3]. It has been reported that paclitaxel at ultra-low non-toxic doses (15 mg/m2) can inhibit inflammatory responses through different mechanisms. For instance, stabilization of endothelial microtubules decreases neutrophil locomotion and leukocyte chemotaxis [4, 5]. Furthermore, paclitaxel down-regulated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, the nuclear factor-κB (NF-κB), and pro-inflammatory cytokines (interleukin-1β [IL-1β], IL-6, IL-10, IL-5, IL-13, tumor necrosis factor α [TNFα], transforming growth factor β [TGFβ], and interferon γ [IFN-γ]) in various non-neoplastic conditions, including endotoxin-induced acute lung injury, Schistosoma mansoni-induced pulmonary hypertension, and sepsis-induced liver injury [6, 7, 8, 9]. SARS-CoV-2 induces cytokine production by activating the NF-кB/ MAPK signaling pathway [10]. Therefore, paclitaxel may be able to inhibit the cytokine storm through the suppression of inflammatory cytokines production.
It is well established that IL-6, one of the critical cytokines in the pathogenesis of COVID-19, leads to proliferation, differentiation, recruitment, and survival of immune cells via activation of the Janus Kinase (JAK) signal transducer and activator of transcription (STAT) pathway [11]. Additionally, the increased expression of the activated form of signal transducer and activator of transcription 3 (STAT3) in the lung up-regulates the pro-inflammatory cytokines and chemokines [12]. It is reported that paclitaxel could decrease the STAT3 and phospho STAT3 (Ser727) levels in human esophageal squamous cell carcinoma (ESCC) [13]. Therefore, blocking the JAK-STAT pathway by paclitaxel is suggested as a therapeutic target for the inhibition of the cytokine storm induced by SARS-CoV-2. 
It is reported that the interaction between SARS-CoV-2 spike protein and toll-like receptor 4 (TLR-4) induces the expression of pro-inflammatory cytokines, and regulates IL-6 secretion through the activation of transcription factors, like NF-κB, AP-1, and MAPK pathway [14]. Inhibition of the TLR4-NF-κB pathway with paclitaxel has been indicated in lipopolysaccharide-induced kidney injury [9]. Moreover, a recent publication has shown that paclitaxel improved survival rates and decreased the levels of cytokines in bronchoalveolar lavage fluid (BALF) by inhibition of the TLR4-NF-κB pathway through MUC1 in mouse and human lung type II epithelial cell [15]. MUC1, a large transmembrane glycoprotein expressed in epithelial cells, has an important anti-inflammatory activity against influenza virus-induced inflammation by suppression of TLR signaling and production of anti-inflammatory cytokines, such as IL-10 [16]. It is possible that paclitaxel by inhibition of TLR4 decreases the levels of inflammatory cytokines in severe COVID-19 patients.
Moreover, the antiviral activity of paclitaxel, such as inhibition of Human Immunodeficiency Virus (HIV)-1 protease, has been reported in some studies [17, 18]. In recent years, the induction of autophagy has been noticed as a new therapeutic target for viral diseases. Although little is known about the role of autophagy in the prevention and treatment of COVID-19, it is documented that the SARS-CoV-2 inhibits the autophagy system from increased self-replication and escape from elimination, which makes an efficient viral dose density for viral pathogenicity [19, 20]. This virus hijacks autophagy through several mechanisms, including, the overproduction of the membrane-associated papain-like protease (PLP2) that interacts with beclin-1 (an autophagy-inducing peptide) and inhibits the fusion of the autophagosome with the lysosome to increase the virus load in host cells. Paclitaxel exerts an inductive effect on autophagy via various mechanisms, such as the increased expression of beclin-1 (an autophagy-inducing peptide) and LC3 (a marker of autophagosome formation) [21]. Also, a previous study demonstrated that beclin-1 prevented the replication and reduced the titers of several positive-stranded RNA viruses, including HIV-1, and improved clinical outcomes [22]. Therefore, paclitaxel may have an antiviral effect against SARS-COV-2 through autophagy-inducing activity. 
Accordingly, the authors suggest that paclitaxel may have therapeutic potential in COVID-19 through anti-inflammatory and possibly antiviral activity; however, clinical trials are yet needed.

Ethical Considerations
Compliance with ethical guidelines

There were no ethical considerations to be considered in this research.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Authors' contributions
Conceived of the presented idea: Saeedeh Shariati and Marzieh Pashmforosh; Collected the data: Hamideh Aghaei Nezhad and Mojtaba Haghighat; Wrote the manuscript with support from: Saeedeh Shariati, Marzieh Pashmforosh and Hamideh Aghaei Nezhad; Read and approved the final manuscript: All authors.

Conflict of interest
The authors declared no conflict of interest.

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Type of Study: Short Communication | Subject: Pharmacology

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