KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts.

Abstract

The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)-Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time- and dose-dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra-bone injection of INA-6 cells to subcutaneously implanted rabbit bones (SCID-rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID-rab model. These results suggest that KRN5500 exerts anti-MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.

• Authors: Hirokazu Miki, Shuji Ozaki, Shingen Nakamura, Asuka Oda, Hiroe Amou, Akishige Ikegame, Keiichiro Watanabe, Masahiro Hiasa, Qu Cui, Takeshi Harada, Shiro Fujii, Ayako Nakano, Kumiko Kagawa, Kyoko Takeuchi, Ken-Ichiro Yata, Akira Sakai, Masahiro Abe, Toshio Matsumoto
• Journal: British journal of haematology (Br J Haematol) Vol. 155 Issue 3 Pg. 328-39 (Nov 2011) ISSN: 1365-2141 [Electronic] England
• PMID: 21902681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2011 Blackwell Publishing Ltd.

Chemical References

• Purine Nucleosides
• KRN 5500
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Bone Marrow Cells (pathology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• G1 Phase (drug effects)
• Humans
• Mice
• Mice, SCID
• Multiple Myeloma (drug therapy, pathology)
• Osteoclasts (drug effects, pathology)
• Purine Nucleosides (pharmacology)
• Rabbits
• Random Allocation
• Stromal Cells (pathology)
• Tumor Microenvironment
• Xenograft Model Antitumor Assays