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

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.

Anisotropic Platinum Nanoparticle-Induced Cytotoxicity, Apoptosis, Inflammatory Response, and Transcriptomic and Molecular Pathways in Human Acute Monocytic Leukemia Cells

“…These findings indicated that the decreased cell viability and damage caused by the NPs ultimately caused the death of the cells [47]. Others also reported that PtNPs induce cytotoxicity through LDH leakage in cancer cells including A549 lung carcinoma, LNCaP prostate cancer, and OS epithelial (U2OS) cells [17,18,47].…”

“…This suggested that lycopene reduced Pt ions and formed stable PtNPs. Others also showed that polyvinylpyrrolidone (PVP) [37], apigenin [22], and tangeretin [18] can reduce Pt and stabilize PtNPs. Figure 1B shows that crystalline PtNPs had the features of a Pt face-centered cubic (fcc) phase.…”

“…Several studies showed that responses to NPs in vitro include cellular death, the activation of stress, inflammatory, and immune responses, cytotoxicity, genotoxicity, developmental abnormalities, the modification of gene transcription, and the modulation of signal transduction pathways [13,14]. Notably, PtNPs are both biocompatible with and cytotoxic to various types of human cells [15][16][17][18]. For instance, PtNPs can act as scavengers of reactive oxygen species (ROS) [19,20], and they induce developmental alterations and increase heart rates in zebrafish [21].…”

“…For instance, PtNPs can act as scavengers of reactive oxygen species (ROS) [19,20], and they induce developmental alterations and increase heart rates in zebrafish [21]. Ultra-small PtNPs induce cellular stress, cytotoxicity, DNA damage, and genotoxicity in vivo and in vitro in human monocytic [22], U2OS [18], and prostate cancer (LNCaP) cell lines [17].…”

“…They induce apoptosis by targeting specific signaling pathways [25], and they induce cytotoxicity in human colon carcinoma HT29 and Caco-2 cell lines, as well as the death of cervical cancer cells through mitotic G2 phase (G2/M) phase arrest [5,26]. Furthermore, PtNPs induce DNA damage in human cancerous and normal cells including colon cancer [27], monocytic [22], U2OS [18], cancer (LNCaP) [17], trophoblasts [28], and bronchial epithelial [29] cells. They also induce apoptosis through G0/G1 cell cycle arrest in the human breast adenocarcinoma cell line, MCF-7 [30].…”