Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells

Abstract

Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS.

Melatonin enhances hyperthermia‐induced apoptotic cell death in human leukemia cells

“…A large number of studies have reported that hyperthermia reduces cell viability mainly through a mechanism that involves induction of apoptosis . The results presented herein demonstrate that melatonin potentiates the apoptotic response in U937 cells exposed to hyperthermia.…”

“…A large number of studies have reported that hyperthermia reduces cell viability mainly through a mechanism that involves induction of apoptosis. 27,53,54 The results presented herein demonstrate that melatonin potentiates the apoptotic response in U937 cells exposed to hyperthermia. In most experiments performed in this study, melatonin was added to cell culture 1 hour before starting hyperthermia; differences in the apoptotic rate were not appreciated with longer preincubation times (3 hours) as well as when the indoleamine was added just at the beginning of heat treatment (data not shown).…”

Hyperthermia adds to trabectedin effectiveness and thermal enhancement is associated with BRCA2 degradation and impairment of DNA homologous recombination repair

“…After heat exposure without trabectedin (41.8 or 43°C), however, we found no significant induction of apoptosis or senescence in SW872 and U2OS. In contrast, hyperthermia alone was shown to induce apoptosis in U2OS beginning at 43°C with remarkably greater amounts of apoptotic cells after temperatures of 45°C and higher . Different heat doses applied or other methodical differences can explain why we detected nearly no induction of apoptosis at 43°C.…”

Polyaniline nanoparticles for near-infrared photothermal destruction of cancer cells

“…In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways (Hou et al 2014). In addition, Yoo et al (2012), demonstrated that ROS-generating magnetic nanoparticles can effectively sensitize cancer cells to make them highly vulnerable to subsequent apoptotic magnetic hyperthermia at low temperatures (43°C).…”