title: Mitochondrial pathway mediates the antileukemic effects of Hemidesmus indicus, a promising botanical drug.
abstract: BACKGROUND
  Although cancers are characterized by the deregulation of multiple signalling pathways, most current anticancer therapies involve the modulation of a single target. Because of the enormous biological diversity of cancer, strategic combination of agents targeted against the most critical of those alterations is needed. Due to their complex nature, plant products interact with numerous targets and influence several biochemical and molecular cascades. The interest in further development of botanical drugs has been increasing steadily and the FDA recently approved the first new botanical prescription drug. The present study is designed to explore the potential antileukemic properties of Hemidesmus indicus with a view to contributing to further development of botanical drugs. Hemidesmus was submitted to an extensive in vitro preclinical evaluation.
  
  
  RESULTS
  A variety of cellular assays and flow cytometry, as well as a phytochemical screening, were performed on different leukemic cell lines. We have demonstrated that Hemidesmus modulated many components of intracellular signaling pathways involved in cell viability and proliferation and altered the protein expression, eventually leading to tumor cell death, mediated by a loss of mitochondrial transmembrane potential and increased Bax/Bcl-2 ratio. ADP, adenine nucleotide translocator and mitochondrial permeability transition pore inhibitors did not reverse Hemidesmus-induced mitochondrial depolarization. Hemidesmus induced a significant [Ca(2+)](i) raise through the mobilization of intracellular Ca(2+) stores. Moreover, Hemidesmus significantly enhanced the antitumor activity of three commonly used chemotherapeutic drugs (methotrexate, 6-thioguanine, cytarabine). A clinically relevant observation is that its cytotoxic activity was also recorded in primary cells from acute myeloid leukemic patients.
  
  
  CONCLUSIONS
  These results indicate the molecular basis of the antileukemic effects of Hemidesmus and identify the mitochondrial pathways and [Ca(2+)](i) as crucial actors in its anticancer activity. On these bases, we conclude that Hemidesmus can represent a valuable tool in the anticancer pharmacology, and should be considered for further investigations.
authors: Department of Pharmacology, Alma Mater Studiorum, University of Bologna, Bologna, Italy. carmela.fimognari@unibo.it
authors: Carmela
authors: C
authors: Fimognari
authors: Monia
authors: M
authors: Lenzi
authors: Lorenzo
authors: L
authors: Ferruzzi
authors: Eleonora
authors: E
authors: Turrini
authors: Paolo
authors: P
authors: Scartezzini
authors: Ferruccio
authors: F
authors: Poli
authors: Roberto
authors: R
authors: Gotti
authors: Alessandra
authors: A
authors: Guerrini
authors: Giovanni
authors: G
authors: Carulli
authors: Virginia
authors: V
authors: Ottaviano
authors: Giorgio
authors: G
authors: Cantelli-Forti
authors: Patrizia
authors: P
authors: Hrelia
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018922:HL-60 Cells; D031102:Hemidesmus / Q000737:chemistry*; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010936:Plant Extracts; D045304:Cytochromes c; D002118:Calcium