title: Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells.
abstract: BACKGROUND
  Traditional medicine plays a major role for primary health care worldwide. Cancer belongs to the leading disease burden in industrialized and developing countries. Successful cancer therapy is hampered by the development of resistance towards established anticancer drugs.
  
  
  OBJECTIVE
  In the present study, we investigated the cytotoxicity of 29 extracts from 26 medicinal plants of South-Africa against leukemia cell lines, most of which are used traditionally to treat cancer and related symptoms.
  
  
  METHODS
  We have investigated the plant extracts for their cytotoxic activity towards drug-sensitive parental CCRF-CEM leukemia cells and their multidrug-resistant P-glycoprotein-overexpressing subline, CEM/ADR5000 by means of the resazurin assay. A panel of 60 NCI tumor cell lines have been investigated for correlations between selected phytochemicals from medicinal plants and the expression of resistance-conferring genes (ABC-transporters, oncogenes, tumor suppressor genes).
  
  
  RESULTS
  Seven extracts inhibited both cell lines (Acokanthera oppositifolia, Hypoestes aristata, Laurus nobilis, Leonotis leonurus, Plectranthus barbatus, Plectranthus ciliates, Salvia apiana). CEM/ADR5000 cells exhibited a low degree of cross-resistance (3.35-fold) towards the L. leonurus extract, while no cross-resistance was observed to other plant extracts, although CEM/ADR5000 cells were highly resistant to clinically established drugs. The log10IC50 values for two out of 14 selected phytochemicals from these plants (acovenoside A and ouabain) of 60 tumor cell lines were correlated to the expression of ABC-transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS) and tumor suppressors (TP53). Sensitivity or resistance of the cell lines were not statistically associated with the expression of these genes, indicating that multidrug-resistant, refractory tumors expressing these genes may still respond to acovenoside A and ouabain.
  
  
  CONCLUSIONS
  The bioactivity of South African medicinal plants may represent a basis for the development of strategies to treat multidrug-resistant tumors either by phytotherapeutic approaches with whole plant preparations or by classical drug development with isolated compounds such as acovenoside A or ouabain.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Mohamed E M
authors.initials: MEM
authors.lastname: Saeed
authors.affiliation: Plant Science Department, University of Pretoria, 002 Pretoria, South Africa.
authors.forename: Marion
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Chemistry Department, University of Western Cape, Private Bag X17, Belleville 7535, South Africa.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hussein
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D019684:Magnoliopsida; D016488:Medicine, African Traditional; D009369:Neoplasms / Q000188:drug therapy; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal; D013019:South Africa
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts
keywords: ABC transporters; Chemotherapy; Multidrug resistance; Natural products; Pharmacogenomics; Phytotherapy