title: Novel cytotoxic isolated from Jamaican Hyptis verticillata jacq induces apoptosis and overcomes multidrug resistance.
abstract: BACKGROUND
  Adult T-cell leukemia is an aggressive hematological malignancy with a poor clinical prognosis, and a rapid resistance to chemotherapy is rapid.
  
  
  METHODS
  Cytotoxicity assay-directed fractionation identified a novel lignan-related agent, 4-methoxy-9-(3,4,5-trimethoxyphenyl)-8, 9 - dihydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5H)-one (4-MTDND) from the Jamaican plant Hyptis verticillata jacq, and its effects on apoptosis, cell cycle and drug resistance were elucidated.
  
  
  RESULTS
  The novel agent, 4-MTDND, exhibited cytotoxicity against myriad cancer types, with a wide therapeutic index of 30- to 40-fold, promoted G(2)/M arrest and up-regulated expression of pro-apoptotic proteins p53 and BAX, as well as enhanced activation of caspase-3, caspase-9 and poly (ADP ribose) polymerase, consistent with apoptosis induction. Multidrug-resistant cancer cells were as susceptible to 4-MTDND as their non-resistant control counterparts, with 4-MTDND having greater efficacy compared to standard chemotherapy agents etoposide and mitoxantrone.
  
  
  CONCLUSIONS
  The novel cytotoxic agent 4-MTDND induces G(2)/M arrest and apoptosis in cancer cells possibly due to direct DNA damage or interference with topoisomerase II.
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8544, Japan.
authors.forename: Yohann
authors.initials: Y
authors.lastname: White
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakashima
authors.forename: Miho
authors.initials: M
authors.lastname: Hachiman
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kozako
authors.forename: Kakushi
authors.initials: K
authors.lastname: Matsushita
authors.forename: Kimiharu
authors.initials: K
authors.lastname: Uozumi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Suzuki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kofune
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Naomichi
authors.initials: N
authors.lastname: Arima
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D003603:Cytotoxins / Q000737:chemistry; D004249:DNA Damage; D004148:Dioxolanes / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D031331:Hyptis / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000188:drug therapy; D017705:Lignans / Q000737:chemistry; D008942:Mitoxantrone / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: C570119:4-methoxy-9-(3,4,5-trimethoxyphenyl)-8,9-dihydrofuro(3',4':6,7)naphtho(2,3-d)(1,3)dioxol-6(5H)-one; D000970:Antineoplastic Agents; D003603:Cytotoxins; D004148:Dioxolanes; D017705:Lignans; D010936:Plant Extracts; D059003:Topoisomerase Inhibitors; D005047:Etoposide; D008942:Mitoxantrone; D011065:Poly(ADP-ribose) Polymerases