GANT61 and Valproic Acid Synergistically Inhibited Multiple Myeloma Cell Proliferation via Hedgehog Signaling Pathway

Zhang, Zhihua; Zhang, Rongjuan; Hao, Chang-Lai; Pei, Xiaochuan; Li, Jundong; Wang, Lihong

doi:10.12659/msm.920541

Cited by 9 publications

(7 citation statements)

References 26 publications

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“…We demonstrated that VPA significantly inhibited the proliferation of HeLa cells in a concentration-and timedependent manner. This finding is consistent with other previous studies indicating the anti-proliferative function of VPA in other tumor cell lines, including glioma (24), multiple myeloma (25), prostate (26), bladder (27), gastric (28), and urothelial (29) cancers. After VPA exposure, decreased cell proliferation in HeLa cells has been previously reported (15,30).…”

Section: Discussionsupporting

confidence: 93%

Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells

et al. 2022

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Background: Valproic acid (VPA), a branched short-chain fatty acid and histone deacetylase (HDAC) inhibitor, has diverse biological activities in human cells, including anti-cancer properties. Objectives: In the present study, we tested the cytotoxicity of VPA on the proliferation, cell cycle, and apoptosis of the human cervical cancer cell line, HeLa. Methods: HeLa cell line was cultured in Dulbecco’s modified eagle medium (DMEM) and the cytotoxicity effect of VPA (at 0 - 100 mM) on the HeLa cell was evaluated, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay for 3 incubation times (24, 48, and 72 h). The effects of VPA on cell cycle arrest and apoptosis were evaluated, using flow cytometry. In addition, the alterations in the expression of Bax, Bcl-2, p53, and p21 were assessed with real‐time polymerase chain reaction (PCR). Results: Valproic acid reduced the viability of HeLa cells in a concentration- and time-dependent manner, and the IC50 values at 24, 48, and 72 h were 32.06, 21.29, and 14.51 mM, respectively. Further, VPA treatment remarkably increased the apoptosis of HeLa cells and arrested cells at the sub-G1 phase with a significant reduction in G2-M phase populations. The real-time PCR results demonstrated a significant increase in the expression of pro-apoptotic genes, including Bax, p53, and p21, as well as a reduction in the levels of the anti-apoptotic gene, Bcl-2. Conclusions: Valproic acid inhibits the proliferation of the HeLa cell line through the induction of the intrinsic pathway of apoptosis in a p35-dependent manner.

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Section: Discussionsupporting

confidence: 93%

Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells

et al. 2022

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“…AdPlus-mCherry-GFP-LC3B adenovirus was also used to transfect cells, based on the principle that in the case of non-autophagy, mCherry-GFP-LC3B is present in the cytoplasm as diffuse yellow fluorescence under fluorescence microscopy, In the case of autophagy, mCherry-GFP-LC3B aggregated on the autophagosome membrane under fluorescence microscope, presenting as yellow spots; When the autophagosome and lysosome fuse, they appear as red spots due to partial quenching of GFP fluorescence. The above experimental results suggest that ursolic acid and GANT61 activate the autophagosome formation phase, but do not inhibit the lysosome fusion degradation phase [ 15 , 16 ]. Currently, hedgehog pathway inhibitors have been widely used as a treatment for various types of cancers caused by pathway overactivation.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Ursolic Acid on Proliferation and Migration of Renal Carcinoma Cells and Its Mechanism

Lyu

Zhang

Sun

et al. 2022

Computational Intelligence and Neuroscience

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Background. Renal carcinoma is one of the most common malignant tumors in the urinary system. Autophagy can be both activated and inhibited in renal carcinoma, and it plays a double-edged role in the development of renal carcinoma. In the early stage of cancer, autophagy can suppress tumors. In the late stage, autophagy contributes to the survival of tumor cells in an unfavorable environment, and some autophagy-related proteins P62, LC3B, and beclin-1 have become indicators of the prognosis of patients with renal carcinoma. Aim. To demonstrate that ursolic acid activates autophagy in renal carcinoma 786-O cells by inhibiting the hedgehog signaling pathway. Methods. The effect of ursolic acid on the viability of 786-O cells was determined by the MTT method; the effect of ursolic acid on the proliferation and migration of 786-O cells was examined by crystalline violet staining and scratch assay, respectively. For the study of autophagy, we firstly screened the time points. Western blot assay was used to detect the expression level of autophagic protein P62 at different time points of ursolic acid on 786-O. Then, the Cell MeterTM Autophagy Assay Kit was used to detect the effect of different doses of ursolic acid on the autophagic fluorescence intensity of 786-O cells; the Western blot method was used to detect the effect of different doses of ursolic acid on the expression levels of LC3II and P62 proteins in 786-O cells. Further, AdPlus-mCherry-GFP-LC3B adenovirus transfection was used to detect the effect of ursolic acid on the autophagic flow of 786-O cells; ursolic acid was combined with the autophagy inhibitor chloroquine (CQ) to detect the expression level of autophagy protein LC3II by Western blot. In terms of mechanism, the effect of ursolic acid on hedgehog signaling pathway-related proteins in 786-O cells was detected by Western blot. Results. Ursolic acid inhibited the activity, proliferation, and migration of 786-O cells, enhanced the fluorescence intensity of autophagosomes in 786-O cells, increased the expression level of autophagy marker protein LC3II, and inhibited the expression level of P62 in a time and dose-dependent manner; ursolic acid activated the autophagic flow in 786-O cells, which showed that ursolic acid caused the accumulation of autophagic fluorescent spots and enhanced the fluorescence intensity of autophagosomes. Ursolic acid activated the autophagic flow in 786-O cells, as evidenced by the accumulation of autophagic fluorescent spots and enhanced fluorescence intensity of autophagosomes, and the combined use of the autophagy inhibitor CQ increased the expression level of LC3II compared to ursolic acid alone; ursolic acid decreased the expression levels of PTCH1, GLI1, SMO, SHH, and c-Myc and increased the expression level of Sufu in the hedgehog signaling pathway. Conclusion. Ursolic acid activates autophagy in renal carcinoma 786-O cells, probably by inhibiting hedgehog signaling pathway activity.

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“…Currently, known inhibitors of the Hedgehog signaling pathway include GANT61, cyclopamine, and GANT58 [ 26 ]. GANT61 specifically blocks GLI1 in the Hedgehog signaling pathway and inhibits cell transcription and expression [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Targeting the Hedgehog Signaling Pathway against Chemotherapeutic Resistance in Multiple Myeloma

Zhang

Yao

Yang

et al. 2022

Journal of Oncology

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Objective. The aim of this study was to explore the relationship between the Hedgehog signaling pathway and drug resistance in multiple myeloma. Methods. The human myeloma cell line RPMI 8266 was taken as the research object. An azithromycin (AZM)-resistant cell line RPMI 8226/R was constructed, and GENT61 was used to block the Hedgehog signaling pathway. Cells were rolled into RPMI 8226/S (S group), RPMI 8226/R (R group), GENT61+RPMI 8226/S (GENT61+S group), and GENT61+RPMI 8226/R (GENT61+R group). The proliferation of cells in each group was assessed, and the expression of patched homolog 1 (PTCH1), zinc finger-containing transcription factors 1 (GLI1), GLI2, hair-division associated enhancer 1 (Hes1), and sonic hedgehog factor (SHH) in each group was detected. Interleukin (IL)-6 and vascular endothelial growth factor (VEGF) were measured. Results. Compared with the S group, the expression levels of PTCH1, GLI2, Hes1, and SHH and the contents of IL-6 and VEGF in the R group were greatly increased, while the expression level of GLI1 was notably decreased ( P < 0.05 ). Compared with the R group, the GENT61+R group greatly increased cell proliferation inhibition. However, the expression levels of PTCH1, GLI2, Hes1, and SHH, and the contents of IL-6 and VEGF were notably decreased, while GLI1 expression levels were greatly increased ( P < 0.05 ). Conclusion. AZM-resistant multiple myeloma was closely associated with the Hedgehog signaling pathway activation, and blocking the Hedgehog signaling pathway can be used as a therapeutic target to improve drug resistance in multiple myeloma.

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GANT61 and Valproic Acid Synergistically Inhibited Multiple Myeloma Cell Proliferation via Hedgehog Signaling Pathway

Cited by 9 publications

References 26 publications

Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells

Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells

Inhibitory Effect of Ursolic Acid on Proliferation and Migration of Renal Carcinoma Cells and Its Mechanism

Mechanism of Targeting the Hedgehog Signaling Pathway against Chemotherapeutic Resistance in Multiple Myeloma

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