Piperine enhances doxorubicin sensitivity in triple-negative breast cancer by targeting the PI3K/Akt/mTOR pathway and cancer stem cells

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Hakeem A.N.; El-Kersh D.M.; Hammam O.; Elhosseiny A.; Zaki A.; Kamel K.; Yasser L.; Barsom M.; Ahmed M.; Gamal M.; Attia Y.M.

Journal: Scientific Reports

Publisher: Nature Research

Publication Date: 6 August 2024

Volume / Issue: Volume 14 / Issue 1

Article No.: 18181

ISSN: 20452322

DOI: 10.1038/s41598-024-65508-0

Scopus: View on Scopus

PubMed: 39107323

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Hakeem A.N., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, Health Research Center of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; El-Kersh D.M., Health Research Center of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, Pharmacognosy Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Hammam O., Pathology Department, Theodor Bilharz Research Institute, Giza, Egypt; Elhosseiny A., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Zaki A., Graduate Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Kamel K., Graduate Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Yasser L., Graduate Students, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Barsom M., Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Ahmed M., Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Gamal M., Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Attia Y.M., Pharmacology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt, Health Research Center of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks an actionable target with limited treatment options beyond conventional chemotherapy. Therapeutic failure is often encountered due to inherent or acquired resistance to chemotherapy. Previous studies implicated PI3K/Akt/mTOR signaling pathway in cancer stem cells (CSCs) enrichment and hence chemoresistance. The present study aimed at investigating the potential effect of piperine (PIP), an amide alkaloid isolated from Piper nigrum, on enhancing the sensitivity of TNBC cells to doxorubicin (DOX) in vitro on MDA-MB-231 cell line and in vivo in an animal model of Ehrlich ascites carcinoma solid tumor. Results showed a synergistic interaction between DOX and PIP on MDA-MB-231 cells. In addition, the combination elicited enhanced suppression of PI3K/Akt/mTOR signaling that paralleled an upregulation in this pathway’s negative regulator, PTEN, along with a curtailment in the levels of the CSCs surrogate marker, aldehyde dehydrogenase-1 (ALDH-1). Meanwhile, in vivo investigations demonstrated the potential of the combination regimen to enhance necrosis while downregulating PTEN and curbing PI3K levels as well as p-Akt, mTOR, and ALDH-1 immunoreactivities. Notably, the combination failed to change cleaved poly-ADP ribose polymerase levels suggesting a pro-necrotic rather than pro-apoptotic mechanism. Overall, these findings suggest a potential role of PIP in decreasing the resistance to DOX in vitro and in vivo, likely by interfering with the PI3K/Akt/mTOR pathway and CSCs. © The Author(s) 2024.

Keywords

Cancer stem cells; Doxorubicin; PI3K/Akt/mTOR; Piperine; PTEN; Triple-negative breast cancer; Alkaloids; Animals; Apoptosis; Benzodioxoles; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Mice; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms; 1,3 benzodioxole derivative; alkaloid; amide; MTOR protein, human; phosphatidylinositol 3 kinase; piperidine derivative; protein kinase B; target of rapamycin kinase; animal; cancer stem cell; drug effect; drug potentiation; drug resistance; drug therapy; human; metabolism; mouse; pathology; triple negative breast cancer; tumor cell line

Citation Information

Scopus Citations: 37

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