title: Cytotoxicity and cell cycle arrest induced by andrographolide lead to programmed cell death of MDA-MB-231 breast cancer cell line.
abstract: BACKGROUND
  Breast cancer is considered as an increasing major life-threatening concern among the malignancies encountered globally in females. Traditional therapy is far from satisfactory due to drug resistance and various side effects, thus a search for complementary/alternative medicines from natural sources with lesser side effects is being emphasized. Andrographis paniculata, an oriental, traditional medicinal herb commonly available in Asian countries, has a long history of treating a variety of diseases, such as respiratory infection, fever, bacterial dysentery, diarrhea, inflammation etc. Extracts of this plant showed a wide spectrum of therapeutic effects, such as anti-bacterial, anti-malarial, anti-viral and anti-carcinogenic properties. Andrographolide, a diterpenoid lactone, is the major active component of this plant. This study reports on andrographolide induced apoptosis and its possible mechanism in highly proliferative, invasive breast cancer cells, MDA-MB-231 lacking a functional p53 and estrogen receptor (ER). Furthermore, the pharmacokinetic properties of andrographolide have also been studied in mice following intravenous and oral administration.
  
  
  RESULTS
  Andrographolide showed a time- and concentration- dependent inhibitory effect on MDA-MB-231 breast cancer cell proliferation, but the treatment did not affect normal breast epithelial cells, MCF-10A (>80 %). The number of cells in S as well as G2/M phase was increased after 36 h of treatment. Elevated reactive oxygen species (ROS) production with concomitant decrease in Mitochondrial Membrane Potential (MMP) and externalization of phosphatidyl serine were observed. Flow cytometry with Annexin V revealed that the population of apoptotic cells increased with prolonged exposure to andrographolide. Activation of caspase-3 and caspase-9 were also noted. Bax and Apaf-1 expression were notably increased with decreased Bcl-2 and Bcl-xL expression in andrographolide-treated cells. Pharmacokinetic study with andrographolide showed the bioavailability of 9.27 ± 1.69 % with a Cmax, of 0.73 ± 0.17 μmol/L and Tmax of 0.42 ± 0.14 h following oral administration. AG showed rapid clearance and moderate terminal half lives (T1/2) of 1.86 ± 0.21 and 3.30 ± 0.35 h following IV and oral administration respectively.
  
  
  CONCLUSIONS
  This investigation indicates that andrographolide might be useful as a possible chemopreventive/chemotherapeutic agent for human breast cancers.
authors.affiliation: Department of Microbiology, University of Kalyani, Kalyani, 741235, WB, India.|TCG Life Science Ltd., Bengal Intelligent Park, Tower-B, Block-EP & GP, Sector-5, Salt Lake, Kolkata, 700091, India.
authors.forename: Malabika
authors.initials: M
authors.lastname: Banerjee
authors.affiliation: TCG Life Science Ltd., Bengal Intelligent Park, Tower-B, Block-EP & GP, Sector-5, Salt Lake, Kolkata, 700091, India.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Department of Biotechnology, Visva-Bharati, Santiniketan, 731235, India.
authors.forename: Tathagata
authors.initials: T
authors.lastname: Choudhuri
authors.affiliation: TCG Life Science Ltd., Bengal Intelligent Park, Tower-B, Block-EP & GP, Sector-5, Salt Lake, Kolkata, 700091, India.
authors.forename: Rammohan
authors.initials: R
authors.lastname: Bera
authors.affiliation: TCG Life Science Ltd., Bengal Intelligent Park, Tower-B, Block-EP & GP, Sector-5, Salt Lake, Kolkata, 700091, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: TCG Life Science Ltd., Bengal Intelligent Park, Tower-B, Block-EP & GP, Sector-5, Salt Lake, Kolkata, 700091, India.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Chakraborty
authors.affiliation: Department of Microbiology, University of Kalyani, Kalyani, 741235, WB, India. dr.samirmukherjee@gmail.com.
authors.forename: Samir Kumar
authors.initials: SK
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D003603:Cytotoxins; D004224:Diterpenes; C030419:andrographolide
keywords: Andrographolide; Apoptosis; Bioanalysis; Breast cancer; Cell cycle arrest; Phytomedicine