Triple negative breast cancer (TNBC) is classically treated with combination chemotherapies. Although, initially responsive to chemotherapies, TNBC patients frequently develop drug-resistant, metastatic disease. Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the therapy-induced senescence (TIS). In this paper, we will focus on chemoresistance in TNBC due to TIS. One of the key characteristics of senescent cells is a complex secretory phenotype, known as the senescence-associated secretory proteome (SASP), which by prompting immune-mediated clearance of senescent cells maintains tissue homeostasis and suppresses tumorigenesis. However, in cancer, particularly with TIS, senescent cells themselves as well as SASP promote cellular reprograming into a stem-like state responsible for the emergence of drug-resistant, aggressive clones. In addition to chemotherapies, outcomes of recently approved immune and DNA damage-response (DDR)-directed therapies are also affected by TIS, implying that this a common strategy used by cancer cells for evading treatment. Although there has been an explosion of scientific research for manipulating TIS for prevention of drug resistance, much of it is still at the pre-clinical stage. From an evolutionary perspective, cancer is driven by natural selection, wherein the fittest tumor cells survive and proliferate while the tumor microenvironment influences tumor cell fitness. As TIS seems to be preferred for increasing the fitness of drug-challenged cancer cells, we will propose a few tactics to control it by using the principles of evolutionary biology. We hope that with appropriate therapeutic intervention, this detrimental cellular fate could be diverted in favor of TNBC patients.
The current COVID-19 pandemic caused by the severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) created a global health crisis. The ability of vaccines to
protect immunocompromised individuals and from emerging new strains are major concerns.
Hence antiviral drugs against SARS-CoV-2 are essential. The SARS-CoV-2 main protease
M
pro
is vital for replication and an important target for antivirals. Using
CMap analysis and docking studies, withaferin A (wifA) and withanone (win), two natural
products from the medicinal herb
Withania somnifera
(ashwagandha), were
identified as promising candidates that can covalently inhibit the viral protease
M
pro
. Cell culture, enzymatic, LC-MS/MS, computational, and equilibrium
dialysis based assays were performed. DFT calculations indicated that wifA and win can
form stable adducts with thiols. The cytotoxicity of M
pro
was significantly
reduced by wifA and win. Both wifA and win were found to irreversibly inhibit 0.5
μM M
pro
with IC
50
values of 0.54 and 1.8 μM,
respectively. LC-MS/MS analysis revealed covalent adduct formation with wifA at
cysteines 145 and 300 of M
pro
. The natural products wifA and win can
irreversibly inhibit the SARS-CoV-2 main protease M
pro
. Based on the work
presented here we propose that both wifA and win have the potential to be safely used as
preventative and therapeutic interventions for COVID-19.
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