Proliferation-Inhibitory and Apoptosis-Inducing Effects of Targeting MTH1 on Multiple Myeloma Cells

Abstract

To detect the expression of MutT homolog 1 (MTH1) in CD138-negative cells (CD138-) and CD138-positive cells (CD138+) cells of the patients with multiple myeloma (MM), and to explore the effect of MTH1 inhibitor TH588 on cell morphology, proliferation and apoptosis of MM cell U266. CD138- and CD138+ cells of MM patients were isolated, and RNA was extracted. The expression of NUDT family was detected by Q-PCR. MM cell line U266 was used to observe the effect of IL-6 on MTH1 expression. Using fluorescence microscopy to observe the morphological changes of U266 after treatment by TH588 for 48 hours. DAPI staining was used to investigate the nuclear change. Luciferase was used to detect the effect of TH588 on U266 cell proliferation. After treatment with TH588 for 48 h, the change of apoptosis in MM U266 cells was detected by flow cytometer. In some MM patients, the expression of MTH1, NUDT2, NUDT5 and NUDT21 in CD138+ cells was higher than that in CD138- (P<0.05). The luciferase report showed that after treatment of U266 cells with TH588, the fluorescence intensity was significantly lower than that of the control group, and the fluorescence intensity decreased with the increase of drug concentration (r=-0.91). IL-6 could increase the expression of MTH1. Fluorescence microscopy showed that after TH588 treatment of U266 cells for 48 hours, the cells appeared shrinking, smaller, and irregular in shape. After DAPI staining, the TH588-treated cells showed apoptosis characteristics, such as nuclear shrinkage, uneven staining, petal, and radial shape. Flow cytometry showed that the proportion of U266 viable cells decreased significantly after treatment with TH588 for 48 h (P<0.05). MTH1 highly expresses in CD138+ cells of some MM patients. MTH1 expression can increase in U266 cells treated by IL-6. The MTH1 inhibitor TH588 possesses proliferation-inhibitory effect and apoptosis-inducing effect on MM cell U266.