Drug repurposing/repositioning, a strategy effectively employed in cancer treatment, can represent a valid alternative. Most drugs considered for repurposing/repositioning in the therapy of the COVID-19 outbreak are commercially available and their dosage and toxicity in humans is well known, due to years (or even decades) of clinical use. This can allow their fast-track evaluation in phase II–III clinical trials, or even within straightforward compassionate use.
Several drugs being re-considered for COVID-19 therapy are or have been used in cancer therapy. Indeed, virus-infected cells are pushed to enhance the synthesis of nucleic acids, protein and lipid synthesis and boost their energy metabolism, in order to comply to the “viral program”. Indeed, the same features are seen in cancer cells, making it likely that drugs interfering with specific cancer cell pathways may be effective as well in defeating viral replication.
The forcedly limited number of drugs briefly described in this review appear to act essentially through selected mechanisms, i.e., a) inhibition of the PI3K/AKT–SGK1/mTOR signaling cascade; b) inhibition of the cytokine storm; and c) inhibition of viral nucleic acid synthesis. The activation of the PI3K/AKT–SGK1/mTOR pathway appears fundamental for supporting the replication of various virus species in the host [17,18,19,20] by boosting their energy metabolism and reactive oxygen species production, especially in the cells of the immune system [101,102]. Therefore, drugs able to interfere with mTORC1 signaling can produce ATP shortage in the cells in which the virus is replicating, characterized by an excess of energy requirements. Such a metabolic pattern is reminiscent of the peculiar setup of the energy metabolism in cancer cells, i.e. Warburg effect [103,104], where a pivotal role is played by the PI3K/AKT–SGK1/mTOR signaling cascade [10,105,106].
Given the above, it is not surprising that all the non-specific antiviral drugs here described, i.e. the anticancer drugs repositionable in COVID-19 therapy deal with energy metabolism and inflammation.
A set of the drugs described here, e.g. those with explicit antiviral effect, can be preferred for the early stages of SARS-CoV-2 infection, while those dedicated to restraining the cytokine response – and without explicit antiviral effect - should be employed, if necessary, at later time points. Anyway, we should always consider that, even if the medications discussed in this review are safely in use in the clinics, the final decision for their administration in COVID-19 for compassionate and urgent use, when in the absence of validated clinical trials, should be taken solely after collegial approval by the clinical team taking care of the patient and under strict clinical surveillance. Indeed, unpredictable toxic side effects can arise, possibly linked with the patient clinical status or to the simultaneous administration of other drugs. Finally, an interesting evaluation on how COVID-19 pandemic will affect the clinical care in the seven comprehensive cancer centers of Cancer Core Europe is discussed in a timely paper . The authors illustrate appropriate guidelines that can transform this pandemic into an opportunity, e.g. for the assessment of the clinical effects of de-escalating anticancer regimens, forcedly imposed in order to prevent or reduce iatrogenic neutropenia and lymphopenia.
We hope that these findings may pave the way for a more comprehensive clinical experimentation on repurposing of ‘old’ drugs to the treatment of COVID-19, a line of research sustained by scant funds but of prime importance to face this new worldwide challenge.
Reference & source Information : https://link.springer.com/
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