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Re-engineering Antimicrobial Peptides into Oncolytics Targeting Drug-Resistant Ovarian Cancers

  • 2020 CMBE Young Innovators issue
  • Published:
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Abstract

Introduction

Bacteria and cancer cells share a common trait—both possess an electronegative surface that distinguishes them from healthy mammalian counterparts. This opens opportunities to repurpose antimicrobial peptides (AMPs), which are cationic amphiphiles that kill bacteria by disrupting their anionic cell envelope, into anticancer peptides (ACPs). To test this assertion, we investigate the mechanisms by which a pathogen-specific AMP, originally designed to kill bacterial Tuberculosis, potentiates the lytic destruction of drug-resistant cancers and synergistically enhances chemotherapeutic potency.

Materials and Methods

De novo peptide design, paired with cellular assays, elucidate structure-activity relationships (SAR) important to ACP potency and specificity. Using the sequence MAD1, microscopy, spectrophotometry and flow cytometry identify the peptide’s anticancer mechanisms, while parallel combinatorial screens define chemotherapeutic synergy in drug-resistant cell lines and patient derived ex vivo tumors.

Results

SAR investigations reveal spatial sequestration of amphiphilic regions increases ACP potency, but at the cost of specificity. Selecting MAD1 as a lead sequence, mechanistic studies identify that the peptide forms pore-like supramolecular assemblies within the plasma and nuclear membranes of cancer cells to potentiate death through lytic and apoptotic mechanisms. This diverse activity enables MAD1 to synergize broadly with chemotherapeutics, displaying remarkable combinatorial efficacy against drug-resistant ovarian carcinoma cells and patient-derived tumor spheroids.

Conclusions

We show that cancer-specific ACPs can be rationally engineered using nature’s AMP toolbox as templates. Selecting the antimicrobial peptide MAD1, we demonstrate the potential of this strategy to open a wealth of synthetic biotherapies that offer new, combinatorial opportunities against drug resistant tumors.

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Acknowledgments

We thank the laboratory of Dr. Joel Schneider at the National Cancer Institute for providing cancer cell lines. We also thank Dr. Matthew Taylor (Penn State University, College of Medicine, Hershey, PA) for donating the NL20 cell line. We thank the laboratories of Dr. Zissis Chroneos (Penn State University, College of Medicine, Hershey, PA), Dr. Pak Kin Wong (Penn State University, PA), and Dr. Kenneth Keiler (Penn State University, PA) for sharing the bacterial strains employed in these studies. We acknowledge and thank the Penn State Microscopy and Cytometry Facility—University Park, PA for assistance with confocal and electron microscopy. We also acknowledge the Penn State X-Ray Crystallography Facility—University Park, PA for use of the CD spectrophotometer. Funding for this research was provided by the Penn State Institute of Energy and the Environment Human Health and the Environment Seed Grant (S.H.M.), NIH:R00CA194309 (K.M.A.), NIH:F31CA236372 (E.S.D.), Penn State College of Engineering Grant (M.R.A.) and Penn State Graduate Research Fellowship (A.W.S.).

Conflict of interest

Authors Matthew R. Aronson, Erika S. Dahl, Jacob A. Halle, Andrew W. Simonson, Rose A. Gogal, Adam B. Glick, Katherine M. Aird and Scott H. Medina declare they have no conflict of interest.

Research Involving Human Rights

No human studies were carried out by the authors for this article. No animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Penn State University, University Park, PA, 16802, USA

    Matthew R. Aronson, Jacob A. Halle, Andrew W. Simonson & Scott H. Medina

  2. Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA, 17033, USA

    Erika S. Dahl & Katherine M. Aird

  3. Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA, 16802, USA

    Rose A. Gogal & Adam B. Glick

  4. Huck Institutes of the Life Sciences, Penn State University, University Park, PA, 16802, USA

    Adam B. Glick & Scott H. Medina

  5. Department of Biomedical Engineering, The Pennsylvania State University, Suite 122, CBE Building, University Park, PA, 16802-4400, USA

    Scott H. Medina

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Aronson, M.R., Dahl, E.S., Halle, J.A. et al. Re-engineering Antimicrobial Peptides into Oncolytics Targeting Drug-Resistant Ovarian Cancers. Cel. Mol. Bioeng. 13, 447–461 (2020). https://doi.org/10.1007/s12195-020-00626-z

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