[Effect of PI3Kδ inhibitor CAL-101 on myeloma cell lines and preliminary study of synergistic effects with other new drugs].

Abstract

OBJECTIVE:

To investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment.

METHODS:

MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ processed by CAL-101 were analyzed by Western blot.

RESULTS:

CAL-101 at concentration of 15, 20, 25, 30 and 40 μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were (33.54 ± 1.23)%, (41.72 ± 1.78)%, (53.67 ± 2.01)%, (68.97 ± 2.11)% and (79.25 ± 1.92)%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ in cell lines and MM primary cells. p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1.

CONCLUSION:

CAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3Kδ protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.

• Authors: Qing Zhang, Bing Xia, Fulian Qu, Tian Yuan, Shanqi Guo, Weipeng Zhao, Qian Li, Hongliang Yang, Yafei Wang, Yizhuo Zhang
• Journal: Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi (Zhonghua Xue Ye Xue Za Zhi) Vol. 35 Issue 10 Pg. 926-30 (Oct 2014) ISSN: 0253-2727 [Print] China
• PMID: 25339332 (Publication Type: Journal Article)

Chemical References

• Boronic Acids
• Phosphoinositide-3 Kinase Inhibitors
• Piperidines
• Protein Kinase Inhibitors
• Purines
• Pyrazines
• Pyrazoles
• Pyrimidines
• Quinazolinones
• ibrutinib
• Bortezomib
• Adenine
• idelalisib

Topics

• Adenine (analogs & derivatives)
• Boronic Acids
• Bortezomib
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Humans
• Multiple Myeloma (pathology)
• Phosphoinositide-3 Kinase Inhibitors
• Piperidines
• Protein Kinase Inhibitors (pharmacology)
• Purines (pharmacology)
• Pyrazines
• Pyrazoles
• Pyrimidines
• Quinazolinones (pharmacology)