Biology subjects

Neumann, C. A.

Publications and source records attributed to Neumann, C. A..

2 recordsLinked to original sources

bioRxiv2025

Endogenous Nitroalkene Exploits Dependence on Autophagy-Lysosome Pathway in PARPi-Resistant TNBC

Lack of DNA double-strand break repair efficiency exquisitely sensitizes cancers to poly-ADP ribose polymerase inhibitors (PARPi). Unfortunately, resistance to PARPi poses an insurmountable challenge for patients. Mechanisms that confer insensitivity to PARPi therapy include enhanced DNA damage repair and autophagy. Natural and non-natural unsaturated fatty acid nitroalkene derivatives (NFA) show anticancer actions that sensitize TNBC cells to PARPi and other DNA-damaging treatments. We reveal that nitro-oleic acid (OA-NO2) re-sensitizes PARPi-resistant TNBC cells to PARPi. RNA-seq analysis of clinically relevant mutBRCA1 PARPi-resistant TNBC cell lines exhibited upregulation in autophagy and lysosomal pathways. Bio-orthogonal analysis identified the autophagy regulator SQSTM1/p62 as a novel OA-NO2 target, alkylating two redox-sensitive Cys residues of p62 (Cys105 and Cys113). These Cys are essential for p62 regulation of autophagy and mimicked the effects of p62 Cys105 and Cys113Ala mutants and when alkylated by OA-NO2 showed impaired p62 oligomerization, degradation, and inhibition of autophagy. Combination treatment of PARPi-resistant TNBC with a PARPi and OA-NO2 synergistically inhibited p62-associated autophagy and lysosome function. These data emphasize the clinical potential of OA-NO2 for treating PARPi-resistant TNBC patients.

pharmacology and toxicology↗

bioRxiv2024

Discovery of cyclic peptide natural product inhibitors of Balamuthia mandrillaris

Balamuthia mandrillaris is a pathogenic free-living amoeba that causes infection of central nervous system, called Balamuthia amoebic encephalitis (BAE), as well as cutaneous and systemic diseases. Patients infected with B. mandrillaris have a high mortality rate due to the lack of effective treatments. A combination of non-optimized antimicrobial drug regimen is typically recommended; however, they have poor parasite activity and can cause various severe side effects. Cyclic peptides exhibit a broad spectrum of antimicrobial activities and lower cytotoxicity. In this study, we evaluated the anti-B. mandrillaris effect of cyclic peptides. The predicted natural product-43 (pNP-43), identified from the SNaPP (Synthetic Natural Product Inspired Cyclic Peptides) library, and its derivates displayed a significant inhibition for B. mandrillaris trophozoites. Eight pNPs had IC50s <5 M. Furthermore, all hit pNPs demonstrated minimal hemolytic and cytotoxic effects on human cells. Our study first indicates the anti-B. mandrillaris effect of cyclic peptides, which provides a new direction for drug development. Further studies of the mechanism of action and in vivo effects will be elucidated to confirm the potency as a treatment for B. mandrillaris infection in the future.

pharmacology and toxicology↗