Shikonin, dually functions as a proteasome inhibitor and a necroptosis inducer in multiple myeloma cells
| Autor: | Masayoshi Tasaki, Yawara Kawano, Kazuya Yoshinaga, Hiroaki Mitsuya, Yukio Ando, Yukimasa Shiotsu, Yutaka Okuno, Hiroyuki Hata, Yoshitaka Kikukawa, Masaki Ri, Shinsuke Iida, Takayuki Nakashima, Naoko Wada, Shiho Fujiwara, Mitsuharu Ueda |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
X-Box Binding Protein 1
Cancer Research Programmed cell death Indoles Necroptosis heat shock protein necroptosis Antineoplastic Agents Apoptosis Regulatory Factor X Transcription Factors Heat Shock Protein Inhibitor Biology Bortezomib Necrosis Cell Line Tumor medicine Humans Inducer Cell Death Dose-Response Relationship Drug Imidazoles Purine Nucleosides Articles Endoplasmic Reticulum Stress Boronic Acids Hsp70 Cell biology DNA-Binding Proteins multiple myeloma proteasome Oncology Drug Resistance Neoplasm Cell culture Pyrazines Proteasome inhibitor Proteasome Inhibitors Naphthoquinones Transcription Factors medicine.drug |
| Zdroj: | International Journal of Oncology |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2014.2804 |
| Popis: | Shikonin (SHK), a natural small agent (MW 288.3), reportedly induces cell death in various tumor cells. We have found that SHK also exerts potent cytocidal effects on human multiple myeloma (MM) cells, but its anticancer mechanism in MM cells remains to be elucidated. SHK at 2.5–5 μM induced apoptosis in seven MM cell lines, including the bortezomib-resistant cell line KMS11/BTZ. The IC50 value of SHK against KMS11/BTZ was comparable to that of a parental cell line KMS11 (1.1 and 1.56 μM, respectively). SHK induces accumulation of ubiquitinated proteins and activates XBP-1 in MM cells, suggesting that SHK functions as a proteasome inhibitor, eventually inducing ER stress-associated apoptosis. SHK increases levels of HSP70/72, which protects cells from apoptosis, and exerts greater cytocidal effects in combination with the HSP70/72 inhibitor VER-155008. At higher concentrations (10–20 μM), SHK induced cell death, which was completely inhibited by a necroptosis inhibitor, necrostatin-1 (Nec-1), while the cytocidal activity was unaffected by Z-VAD-FMK, strongly suggesting that cell death is induced by SHK at high concentrations through necroptosis. The present data show for the first time that SHK induces cell death in MM cells. SHK efficiently induces apoptosis and combination of heat shock protein inhibitor with low dose SHK enhances apoptosis, while high dose SHK induces necroptosis in MM cells. These findings together support the use of SHK as a potential therapeutic agent for MM. |
| Databáze: | OpenAIRE |
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