chrysin and Osteosarcoma

Identifying novel curative and preventive approaches that can specifically target the osteosarcoma cells (OS) without affecting the normal cells is appreciable. The aim of this study is to investigate the combined effect of chrysin as an apigenin analog with high therapeutic potential and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the treatment of Saos-2 and MG-63 cells. Cell viability were determined using MTT method. The rate of apoptosis was assessed by enzyme-linked immunosorbent assay (ELISA) cell death assay and caspase 8 activity assays. The messenger RNA (mRNA) and protein evaluation of candidate genes include Bcl-2, XIAP, c-IAP1, c-IAP2, and c-FLIP were accomplished before and after the treatment by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. Our results showed that chrysin synergistically increased the cytotoxic effects of TRAIL as follows: Chrysin plus TRAIL > TRAIL > Chrysin. Chrysin could sensitize both cells against the TRAIL-induced apoptosis, amplify the caspase 8 activity and this outcome is achieved by decreasing the expression levels of antiapoptotic genes. Our findings suggest that Chrysin can sensitize the OS cell lines against TRAIL through induction of the death receptor pathway. Moreover, the combinational therapy of these agents might be the promising therapeutic regimen for improving the clinical efficacy of TRAIL-induced apoptosis in patients with OS.

Topics: Apigenin; Apoptosis; Bone Neoplasms; Caspase 8; Cell Line, Tumor; Flavonoids; Humans; Ligands; Osteosarcoma; Proto-Oncogene Proteins c-bcl-2; Receptors, Death Domain; RNA, Messenger; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Vanadium complexes were studied during recent years and considered as a representative of a new class of non-platinum metal antitumor agents in combination with their low toxicity. However, a few challenges still remain in the discovery of new molecular targets for these novel metal-based drugs. The study of cell signaling pathways related to vanadium drugs, which is highly critical for identifying specific targets that play an important role in the antitumor activity of vanadium compounds, is scarce. This research deals with the alterations in intracellular signaling pathways promoted by an oxovanadium(iv) complex with the flavonoid chrysin [VO(chrysin)2EtOH]2 (VOChrys) in a human osteosarcoma cell line (MG-63). Herein we report for the first time the effect of [VO(chrysin)2EtOH]2 on the relative abundance of 224 proteins, which are involved in the most common intracellular pathways. Besides, full-length human recombinant (FAK and AKT1) kinases are produced using an in situ IVTT system and then we have evaluated the variation of relative tyrosine-phosphorylation levels caused by the [VO(chrysin)2EtOH]2 compound. The results of the differential protein expression levels reveal that several proteins such as PKB/AKT, PAK, DAPK, Cdk 4, 6 and 7, FADD, AP2, NAK, and JNK, among others, were altered. Moreover, cell signaling pathways related to the PTK2B, FAK, PKC families suggests an important role associated with the antitumor activity of [VO(chrysin)2EtOH]2 was demonstrated. Finally, the effect of this compound on in situ expressed FAK and AKT1 is validated by determining the phosphorylation level, which decreased in the former and increased in the latter.

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Survival; Flavonoids; Humans; Molecular Structure; Organometallic Compounds; Osteosarcoma; Signal Transduction; Tumor Cells, Cultured; Vanadates

Osteosarcoma (OS) is the most common primary tumor of bone, occurring predominantly in the second decade of life. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for patients with localized disease. Vanadium is an ultra-trace element that after being absorbed accumulates in bone. Besides, vanadium compounds have been studied during recent years to be considered as representative of a new class of non-platinum antitumor agents. Moreover, flavonoids are a wide family of polyphenolic compounds that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, the in vitro and in vivo effects of an oxidovanadium(IV) complex with the flavonoid chrysin on the new 3D human osteosarcoma and xenograft osteosarcoma mice models. The pharmacological results show that VOchrys inhibited the cell viability affecting the shape and volume of the spheroids and VOchrys suppressed MG-63 tumor growth in the nude mice without inducing toxicity and side effects. As a whole, the results presented herein demonstrate that the antitumor action of the complex was very promissory on human osteosarcoma models, whereby suggesting that VOchrys is a potentially good candidate for future use in alternative antitumor treatments.

Topics: Animals; Bone Neoplasms; Cell Culture Techniques; Cell Line, Tumor; Cell Survival; Coordination Complexes; Female; Flavonoids; Humans; Male; Mice, Nude; Microscopy, Phase-Contrast; Molecular Structure; Osteosarcoma; Spheroids, Cellular; Time Factors; Treatment Outcome; Vanadium; Xenograft Model Antitumor Assays

Flavonoids, a polyphenolic compound family, and the vanadium compounds have interesting biological, pharmacological, and medicinal properties. We report herein the antitumor actions of the complex [VO(chrysin)2EtOH]2 (VOchrys) on the MG-63 human osteosarcoma cell line. Oxovanadium(IV), chrysin and VOchrys caused a concentration-dependent inhibition of cell viability. The complex was the strongest antiproliferative agent (p < 0.05). Cytotoxicity and genotoxicity studies also showed a concentration effect. Reactive oxygen species (ROS) and the alterations in the GSH/GSSG ratio underlie the main mechanisms of action of VOchrys. Additions of ROS scavengers (vitamin C plus vitamin E) or GSH to the viability experiments demonstrated beneficial effects (p < 0.01). Besides, the complex triggered apoptosis, disruption of the mitochondria membrane potential (MMP), increased levels of caspase 3 and DNA fragmentation measured by the sub-G1 peak in cell cycle arrest experiments (p < 0.01). Collectively, VOchrys is a cell death modulator and a promissory complex to be used in cancer treatments.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; Humans; Molecular Structure; Organometallic Compounds; Osteosarcoma; Oxidative Stress; Structure-Activity Relationship; Vanadates