Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses.

Abstract

BACKGROUND:

Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known.

PURPOSE:

We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA.

STUDY DESIGN:

Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells.

METHODS:

The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting.

RESULTS:

Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis.

CONCLUSION:

CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.

• Authors: Nuha Mahmoud, Mohamed E M Saeed, Yoshikazu Sugimoto, Anette Klinger, Edmond Fleischer, Thomas Efferth
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 77 Pg. 153271 (Oct 2020) ISSN: 1618-095X [Electronic] Germany
• PMID: 32659679 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier GmbH. All rights reserved.

Chemical References

• ABCB5 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Abietanes
• Antineoplastic Agents, Phytogenic
• Neoplasm Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• EGFR protein, human
• ErbB Receptors
• salvin

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (metabolism)
• Abietanes (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects, physiology)
• ErbB Receptors (genetics, metabolism)
• Humans
• Neoplasm Proteins (metabolism)
• Pharmacogenetics
• Tumor Suppressor Protein p53 (genetics, metabolism)