title: The Role of Monocarboxylate Transporters and Their Chaperone CD147 in Lactate Efflux Inhibition and the Anticancer Effects ofTerminalia chebulain Neuroblastoma Cell Line N2-A.
abstract: OBJECTIVE
  In the presence of oxygen, most of the synthesized pyruvate during glycolysis in the cancer cell of solid tumors is released away from the mitochondria to form lactate (Warburg Effect). To maintain cell homeostasis, lactate is transported across the cell membrane by monocarboxylate transporters (MCTs). The major aim of the current investigation is to identify novel compounds that inhibit lactate efflux that may lead to identifying effective targets for cancer treatment.
  
  
  METHODS
  In this study, 900 ethanol plant extracts were screened for their lactate efflux inhibition using neuroblastoma (N2-A) cell line. Additionally, we investigated the mechanism of inhibition for the most potent plant extract regarding monocarboxylate transporters expression, and consequences effects on viability, growth, and apoptosis.
  
  
  METHODS
  The potency of lactate efflux inhibition of ethanol plant extracts was evaluated in N2-A cells by measuring extracellular lactate levels. Caspase 3- activity and acridine orange/ethidium bromide staining were performed to assess the apoptotic effect. The antiproliferative effect was measured using WST assay. Western blotting was performed to quantify protein expression of MCTs and their chaperone CD147 in treated cells lysates.
  
  
  RESULTS
  Terminalia chebulaplant extract was the most potent lactate efflux inhibitor in N2-A cells among the 900 - tested plant extracts. The results obtained show that extract ofTerminalia chebulafruits (TCE) significantly (P= 0.05) reduced the expression of the MCT1, MCT3, MCT4 and the chaperone CD147. The plant extract was more potent (IC50of 3.59 ± 0.26 μg/ml) than the MCT standard inhibitor phloretin (IC5076.54 ± 3.19 μg/ml). The extract also showed more potency and selective cytotoxicity in cancer cells than DI-TNC1 primary cell line (IC507.37 ± 0.28 vs. 17.35 ± 0.19 μg/ml). Moreover,TCEInhibited N2-A cell growth (IG50= 5.20 ± 0.30 μg/ml) and induced apoptosis at the 7.5 μg/ml concentration.
  
  
  CONCLUSIONS
  Out of the 900 plant extracts screened,Terminalia chebulaethanol extract was found to be the most potent lactate efflux inhibitor with the ability to inhibit chaperone CD147 expression and impact the function of monocarboxylate transporters. Furthermore, TCE was found to have growth inhibition and apoptotic effects. The results obtained indicate thatTerminalia chebulaconstituent(s) may contain promising compounds that can be useful in the management of neuroblastoma cancer.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Messeha
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: N O
authors.initials: NO
authors.lastname: Zarmouh
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: E
authors.initials: E
authors.lastname: Taka
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Gendy
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Shokry
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Kolta
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
authors.forename: K F A
authors.initials: KF
authors.lastname: Soliman
keywords: CD 147; Plant ethanol extracts; apoptosis; growth inhibition; lactate inhibitor; monocarboxylate transporters