Tangeretin-Assisted Platinum Nanoparticles Enhance the Apoptotic Properties of Doxorubicin: Combination Therapy for Osteosarcoma Treatment.

Sangiliyandi Gurunathan,Min-Hee Kang,Muniyandi Jeyaraj,Jin-Hoi Kim

doi:10.3390/nano9081089

Abstract

Osteosarcoma (OS) is the most common type of cancer and the most frequent malignant bone tumor in childhood and adolescence. Nanomedicine has become an indispensable field in biomedical and clinical research, with nanoparticles (NPs) promising to increase the therapeutic efficacy of anticancer drugs. Doxorubicin (DOX) is a commonly used chemotherapeutic drug against OS; however, it causes severe side effects that restrict its clinical applications. Here, we investigated whether combining platinum NPs (PtNPs) and DOX could increase their anticancer activity in human bone OS epithelial cells (U2OS). PtNPs with nontoxic, effective, thermally stable, and thermoplasmonic properties were synthesized and characterized using tangeretin. We examined the combined effects of PtNPs and DOX on cell viability, proliferation, and morphology, reactive oxygen species (ROS) generation, lipid peroxidation, nitric oxide, protein carbonyl content, antioxidants, mitochondrial membrane potential (MMP), adenosine tri phosphate (ATP) level, apoptotic and antiapoptotic gene expression, oxidative stress-induced DNA damage, and DNA repair genes. PtNPs and DOX significantly inhibited U2OS viability and proliferation in a dose-dependent manner, increasing lactate dehydrogenase leakage, ROS generation, and malondialdehyde, nitric oxide, and carbonylated protein levels. Mitochondrial dysfunction was confirmed by reduced MMP, decreased ATP levels, and upregulated apoptotic/downregulated antiapoptotic gene expression. Oxidative stress was a major cause of cytotoxicity and genotoxicity, confirmed by decreased levels of various antioxidants. Furthermore, PtNPs and DOX increased 8-oxo-dG and 8-oxo-G levels and induced DNA damage and repair gene expression. Combination of cisplatin and DOX potentially induce apoptosis comparable to PtNPs and DOX. To the best of our knowledge, this is the first report to describe the combined effects of PtNPs and DOX in OS.

Highlights

Osteosarcoma (OS) is a malignant primary bone tumor commonly observed worldwide in both children and adults, accounting for 60% of primary bone cancers diagnosed under the age of 20 [1]
Al-Radadi et al [30] reported that the plasmon resonance values of platinum NPs (PtNPs) produced using Ajwa and Barni dates were 321 and 329 nm, respectively; the values depended on the size and shape of the PtNPs [31,32,33]
Our findings agree with this study and a previous report showing that AgNPs induce morphological changes in human cervical cancer cells [55]. These results clearly suggest that the toxic effects exerted by PtNPs and DOX-sensitize U2OS cells to the toxic effects of PtNPs and DOX, that the cytotoxic effect of PtNPs and DOX could be due to their antineoplastic nature and ability to induce cell death via numerous molecular mechanisms, and that the combination of PtNPs and DOX could induce U2OS cell apoptosis

Summary

Introduction

Osteosarcoma (OS) is a malignant primary bone tumor commonly observed worldwide in both children and adults, accounting for 60% of primary bone cancers diagnosed under the age of 20 [1]. OS may occur at any age and is thought to occur more often in males than females [2]. The most common, currently-approved treatments for OS are chemotherapy and surgery [3,4]. Neoadjuvant and adjuvant chemotherapy combined with surgery increase the five-year survival rate compared to surgery alone [3,4]; patients with advanced stages of OS exhibit low survival rates [1]. The success rate of surgery alone against localized OS ranges from 15–20%, yet increases to approximately 70% when combined with chemotherapy [5]. There are several primary and adjuvant chemotherapeutic agents used to treat OS, doxorubicin (DOX), cisplatin, and methotrexate are the most common; discovering and developing novel biocompatible agents with less toxic side effects to improve the survival rates of patients is highly important in the field of nanomedicine

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Conclusion