A comparison of apoptosis and necrosis induced by ent-kaurene-type diterpenoids in HL-60 cells

Planta Med. 2004 May;70(5):401-6. doi: 10.1055/s-2004-818966.

Abstract

We previously reported that ent-11alpha-hydroxy-16-kauren-15-one (KD) induces apoptosis through a caspase-dependent pathway and the induction of apoptosis is dependent on its enone group in human leukemia cells. Here we investigated the abilities of some KD-related compounds with enone group (Fig. 1) to induce apoptosis and to activate some caspases. The IC50 values of ent-kaurene-related compounds possessing the enone group, ent-1beta-hydroxy-9(11),16-kauradien-15-one (1), ent-9(11),16-kauradiene-12,15-dione (2) and the rearranged ent-kaurane-type diterpene (3), against HL-60 cells after 12 h of treatment were 40 microM, 1.8 microM and 5.5 microM, respectively. Although treatment with 3 induced apoptosis, DNA ladder formation was not observed after treatment with 1 or 2. Induction of necrosis, as assayed by trypan blue staining, was observed after treatment with 1 or 2. Treatment with compound 1, 2 or 3 induced proteolysis of poly(ADP-ribose) polymerase (PARP), a substrate of caspase-3, and processing of caspase-3. Activation of caspase-8 and processing of Bid, a typical substrate of caspase-8, were also observed on treatment with these compounds. Pretreatment with a broad-spectrum inhibitor of caspases attenuated apoptosis induced by 3 but not necrosis induced by 1 and 2. In summary, KD-related compounds are a unique family of diterpenes that cause either caspase-dependent apoptotic or necrotic cell death.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Apoptosis / drug effects*
  • Diterpenes, Kaurane / administration & dosage
  • Diterpenes, Kaurane / pharmacology*
  • Diterpenes, Kaurane / therapeutic use
  • HL-60 Cells / drug effects
  • Hepatophyta*
  • Humans
  • Inhibitory Concentration 50
  • Necrosis
  • Phytotherapy*
  • Plant Extracts / administration & dosage
  • Plant Extracts / pharmacology*
  • Plant Extracts / therapeutic use

Substances

  • Antineoplastic Agents, Phytogenic
  • Diterpenes, Kaurane
  • Plant Extracts