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  • br Conclusions br Two lipid

    2020-08-30


    4. Conclusions
    Two lipid-modified cationic peptides, Str-H8R8 and VES-H8R8, were selectively cytotoxic to multi-drug resistant breast cancer cells in the low micromolar range, with VES-H8R8 showing greater selectivity and drug efflux inhibition. Similar to other cationic amphiphilic structures, lipid-modified cationic peptides target, disrupt and depolarize mi-tochondria, inhibit mitochondrial bioenergetics, decrease Pgp efflux, and induce ROS production. This leads to apoptosis and/or necrosis, and G1 Erastin arrest. These properties of VES-H8R8 suggest its utility for chemotherapeutic delivery to MDR cancer cells in terms of en-hanced uptake, retention, and anti-cancer activity. r> Acknowledgments
    We are grateful to the Shoichet Lab for thoughtful review and to the 
    following for funding: Natural Sciences and Engineering Research Council of Canada (NSERC Discovery to MSS [RGPIN-2019-06933], NSERC CREATE M3 to PCC [CREAT 432258-13]) and Canadian Institutes of Health Research (CIHR Foundation to MSS [FDN-143276]).
    Appendix A. Supplementary data
    References
    219  BASIC SCIENCE
    Nanomedicine: Nanotechnology, Biology, and Medicine
    Original Article nanomedjournal.com
    Cationic lipoplexes for treatment of cancer stem cell-derived murine lung tumors
    Terrick Andey, PhDa, Namrata Bora-Singhal, PhDb, Srikumar P. Chellappan, PhDb, Mandip Singh, PhDc, aDepartment of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences University, 19 Foster Street, Worcester, MA 01608, USA bDepartment of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA cCollege of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
    Abstract
    Side population (SP) cells with stem-like properties, also known as cancer stem cells (CSC) have been recognized as drivers of the resistance phenotype in many cancers. Central to the characteristic stem-like phenotype of CSCs in cancer is the activity of the SOX2 transcription factor whose upregulation has been associated with enrichment of many oncogenes. This study outlines the fabrication of a lipoplex of SOX2 small interfering RNA (CL-siSOX2) for targeted treatment of SOX2-enriched, CSC-derived orthotopic and xenograft lung tumors in CB-17 SCID mice. CL-siSOX2 induced tumor contraction in cisplatin-naïve and cisplatin-treated groups by 85% and 94% respectively. Reduction in tumor weight and volume following treatment with CL-siSOX2 was associated with reduced protein expression of SOX2 and markers of tumor initiation, inflammation, invasion and metastasis in mice tumor xenografts. In addition, histological staining of lung tumor sections showed reduction in SOX2 expression was associated with inhibition markers of epithelial-to-mesenchymal transition. © 2019 Published by Erastin Elsevier Inc.
    Key words: Nanoparticles; Cationic lipoplex; SOX2 siRNA; Gene delivery; Cancer stem cells; Lung cancer
    Lung cancer is the leading cause of cancer-related deaths globally. In 2017, it was estimated that lung cancer diagnosis and deaths accounted for 13.2% and 25.9% respectively of the national cancer statistics in the United States (https://seer.cancer. gov/csr/1975_2014/). Effective treatment of lung cancer is hindered by severe adverse effects and acquired resistance due to lack of specificity of therapies, and up-regulation of and/or mutations in oncogenes respectively. Acquired tumor resistance is a complex process that is driven by the dynamic nature of cancer cells to sustain proliferation and evade cell death.1 Importantly, up-regulation and/or mutation of oncogenes have been shown to drive the resistance phenotype to more advanced intractable stages of tumor growth.1 The identification and therapeutic targeting of these oncogenes forms the basis of a new approach to cancer treatment known as targeted therapy.
    Conflict of Interest: Authors have no conflicts of interest. Corresponding author at: Mandip Singh Sachdeva, Department of Pharmaceutics, Florida A&M University, Tallahassee, FL 32307, USA.
    E-mail addresses: [email protected] [email protected] (M. Singh).
    A subset of tumor cells has been recognized as enabling replicative immortality in many tumor types including lung tumors. These side populations (SPs) are also known as cancer stem cells (CSCs) because they share similar properties such as self-renewal and pluripotency with embryonic stem cells.2 The CSC theory adduces a critical role for CSCs in promoting metastasis of cancer and enabling drug resistance.3 These CSCs are characterized by low cell cycling potentials, which enable them to escape most cytotoxic therapies that target rapidly dividing cells. CSCs from different types of cancer have been widely characterized to overexpress embryonic stemness factors including SOX2, OCT4, Nanog, and KLF4, as well as multidrug resistance markers including c-Myc, P-glycoprotein, MRP1–6 and ABCG2.4–6