A comparison of apoptosis and necrosis induced by ent-kaurene-type diterpenoids in HL-60 cells.
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.
Suzuki
Ikue
I
Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Japan.
Kondoh
Masuo
M
Nagashima
Fumihiro
F
Fujii
Makiko
M
Asakawa
Yoshinori
Y
Watanabe
Yoshiteru
Y
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045786:Diterpenes, Kaurane / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018922:HL-60 Cells / Q000187:drug effects; D035926:Hepatophyta; D006801:Humans; D020128:Inhibitory Concentration 50; D009336:Necrosis; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; D010936:Plant Extracts