Fangchinoline suppresses the proliferation, invasion and tumorigenesis of human osteosarcoma cells through the inhibition of PI3K and downstream signaling pathways

Abstract

Osteosarcoma is the most common malignant bone tumor. Most patients diagnosed with osteosarcoma are less than 20 years of age. Osteosarcoma cells proliferate rapidly and invade other tissues. At present, neoadjuvant chemotherapy is the primary pharmacodynamic strategy to prevent the progression of osteosarcoma. However, adverse effects of this strategy limit its long-term application. Previous research has shown that fangchinoline exerts antitumor effects on several types of tumor cells; however, its effect on osteosarcoma cells remains unknown. The present study evaluated the effects of fangchinoline on the proliferation, apoptosis, migration and invasion of osteosarcoma cells in vitro and on their tumorigenesis in vivo and determined the possible underlying mechanism of action. Fangchinoline-treated MG63 and U20S cells showed significantly decreased proliferation and significantly increased apoptosis. Fangchinoline markedly suppressed the migration and invasion of the MG63 cells. Fangchinoline-treated MG63 cells showed significantly decreased expression of phosphoinositide 3-kinase (PI3K) and Aktp-Thr308. Moreover, fangchinoline-treated MG63 cells showed downregulated expression of cyclin D1 and matrix metalloproteinase 2 and 9, which act downstream of PI3K, and upregulated expression of caspase-3 and caspase-8. Furthermore, fangchinoline suppressed the growth of subcutaneous osteosarcoma tumors in Balb/c mice subcutaneously injected with osteosarcoma cells. These findings suggest that fangchinoline inhibits the progression of osteosarcoma by suppressing the proliferation, migration and invasion and by accelerating the apoptosis of osteosarcoma cells. In addition, our results suggest that the mechanism underlying the antitumor effects of fangchinoline involve the inhibition of PI3K and its downstream signaling pathways.

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of Stephania tetrandra S. Moore (Fen Fang Ji)

“…As a result of the structural similarity with tetrandrine (9), fangchinoline (10) also has significant antitumor activity in various types of cancers, including carcinoma of the breast (Wang et al 2014b(Wang et al , 2017b, prostate (Li et al 2015b), bladder (Fan et al 2017), lung (Luo et al 2016), stomach (Chen et al 2017b), pancreas (Lee et al 2017) and liver . It also acts against osteosarcoma (Li et al 2017b), glioblastoma (Guo et al 2016), melanoma (Shi et al 2017) and chronic myelogenous leukemia (Wang et al 2018). Still and all, additional investigation using in vivo models with appropriate positive controls, dose, and standards is required.…”

“…A number of mechanisms are involved in the manner in which the constituents of S. tetrandra act against various carcinoma cells, including induction of tumor cell apoptosis (Zhu et al 2014;Bai et al 2018;Liu et al 2017b;Chen et al 2014;Wang et al 2017b;Fan et al 2017), tumor cell autophagy (Zhang et al 2018b;Lien et al 2017;Huang et al 2013;Bai et al 2018;Guo and Pei 2019;Fan et al 2017;Gao et al 2017), tumor cell cycle blockade (Singh et al 2018;Chen et al 2014;Luo et al 2016;Gao et al 2017) and inhibition of tumor cell invasion and metastasis (Zhang et al 2018a;Li et al 2017b;Shi et al 2017). Reversal of multidrug resistance is an additional important mechanism of the anticancer effects of tetrandine (9) and fangchinoline (10).…”

Molecular Targets Modulated by Fangchinoline in Tumor Cells and Preclinical Models

“…Fangchinoline is a traditional chinese medicine isolated from the dried root of Stephaniae tetrandrine S. Moore (family-menispermaceae) [ 24 ]. This bisbenzylisoquinoline alkaloid ( Figure 1 ) showed significant anti-cancer effects in several tumor cell lines, including MDA-MB-231 breast cancer cells [ 25 , 26 , 27 ], MG63 and U20S bone cancer cell lines [ 28 ], A549 lung cancer cell lines [ 29 ], PC3 human prostate cancer cell lines [ 30 ], K562 myelogenous leukemia cells [ 31 ], T24 and 5637 bladder cancer cell lines [ 32 ], human gastric cancer cells AGS [ 33 ], and U87 MG and U118 MG glioblastoma multiforme cancer cell lines [ 34 ].…”

“…Fangchinoline has been reported to exhibit potent anti-proliferation effects against several types of tumor cells. Its anti-proliferative activity and effect on various regulators of cell growth has been substantiated in a variety of malignant cells, including bone cancer/osteosarcoma (MG63 and U20S) [ 28 ], breast cancer (MDA-MB-231) [ 25 , 27 ], and lung adenocarcinoma (SPC-A-1) [ 36 ] by various methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) assay, flow cytometric analysis, Western blot, and reverse transcription polymerase chain reaction (RT-PCR) techniques.…”

“…Preoperative chemotherapy is the current treatment option, but it has a limited long-term effect to prevent the progression of disease. Fangchinoline was found to significantly decrease the proliferation of MG63 and U20S bone cancer cell lines, along with the suppression of migration of MG63 cells [ 28 ]. In MDA-MB-231 as well as SPC-A-1 cells, a time-dependent significant inhibition of cell proliferation has been shown following treatment with fangchinoline [ 25 , 36 ].…”