Drugs-COVID-19: Memorial Sloan Kettering Cancer Center Suggest Using PI3K/mTOR And Topoisomerase Inhibitors To Reduce ACE2 Expression And COVID-19 Risk

Drugs-COVID-19: Researchers from Memorial Sloan Kettering Cancer Center-New York in a new study suggest that using drugs such as PI3K/mTOR And Topoisomerase inhibitors reduces ACE2 expression and reduces risk and an individual’s susceptibility to the SARS-CoV-2 coronavirus that causes the COVID-19 disease.


 
As ACE2 are the main and first receptors that the SARS-CoV-2 coronavirus uses to gain access into the human host cells, reducing their expression especially in the airways etc would help to reduce the risk for COVID-19.
 
The research findings are published on a preprint server and have yet to be peer reviewed. https://www.medrxiv.org/content/10.1101/2020.09.02.20186783v1
 
PI3K/mTOR Inhibitors includes drugs like Sirolimus, also known as rapamycin, which  is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection and treat a rare lung disease called lymphangioleiomyomatosis. It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants.
 
Topoisomerase inhibitors are drugs that block the action of topoisomerase I and II, which are enzymes that control the changes in DNA structure  by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.
 
Topoisomerases are popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death.Topoisomerase inhibitors can also function as antibacterial agents.
 
Topoisomerase I  inhibitors includes drugs like irinotecan,  topotecan,  amptothecin, diflomotecan and lamellarin D, Topoisomerase II inhibitors include drugs like etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone,  ellipticines and HU-331, a quinone synthesized from cannabidiol.
 
Numerous plant derived natural phenols such as genistein,  quercetin,  resveratrol)  possess strong topoisomerase inhibitory properties affecting both types of enzymes.
 
Past research have shown that ACE2 expression on a set of cell lines is linked to the in vitro susceptibility of the given cell to the SAR-CoV-2 coronavirus. Also, since the enzymes in this viral attachment and entry are not known to provide any vital function in the human host, it should be easy to target them without cytotoxic host effects.
 
The study team used a drug library, namely, the Library of Integrated Network-Based Cellular Signatures (LINCS) program, an open resource containing the expression profiles of cells exposed to several agents that disrupt normal cell activity.
 
The team  evaluated the gene expression patterns found in association w ith different drug exposures in LINCS for over 1,800 drugs for which the cell interactions were available at varying doses, from 0.01 uM to 10 uM, across seven cell lines.
 
The researchers were able to identify two major drug classes, which showed the highest reduction in ACE2 expression, namely, topoisomerase inhibitors and PI3K/mTOR pathway inhibitors. The former was found to be associated with the most significant fall in ACE2 expression, and often this was proportional to the dose, as was also the case with PI3K/mTOR inhibitors. The former includes drugs like camptothecin, SN-38, and Genz-644282, while the latter, including PF- 04691502, GDC-0980(RG7422), and Taselisib, also showed reduced ACE2 expression, in direct correlation to the dose. Two AKT inhibitors, which also are involved in the PI3K/mTOR pathway, Afuresertib, and MK-2206, also cause lower ACE2 expression.
 
The study team also looked at whether cancer patients who were treated with drugs that reduced ACE2 expression had lower odds of testing positive for the virus compared to cancer patients on other drugs.
 
Significantly in this retrospective clinical review, they found that among 535 patients on these ACE2-suppressing drugs, the odds of testing positive for the virus were 35% lower than with other anti-neoplastic drugs.
 
Other covariates that were associated with higher odds of positive COVID-19 testing included belonging to a non-white race, at twice the odds; having blood cancer, at almost three times the odds; and metastatic disease, at over 1.5 times the odds. This showed that several cytotoxic agents are able to reduce ACE2 expression, and thus potentially prevent or treat the infection. The actual effect of taking these drugs on the course of the infection in these patients is unknown since in all cases, they were withheld once the patient tested positive for SARS-CoV-2.
 
The study findings agree with earlier studies that have proposed the use of these drugs for the treatment of COVID-19, such as a combination of irinotecan and etoposide for critically ill patients with this condition. This was based on the recorded capacity of these drugs to regulate immunity and viral suppression. In addition, it has been shown that some topoisomerases are essential for the virus to replicate. https://www.preprints.org/manuscript/202003.0341/v1
 
The study noted that the research is based on the computer-modeled reduction of ACE2 by these drugs, and not on experimental results.
 
Also they said that clinical validation is required for the concept that ACE2 expression is a therapeutic target.
 
Another study limitation was that the clinical data was too sparse to allow the impact of this therapy to be estimated in real terms.
 
However the study team said that these drugs are worthy of further study as potential COVID-19 preventives.
 
It should be also noted that almost all the researchers in the study team were affiliated in one way or another to various drug and pharmaceutical companies.
 
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