Glutathione Ameliorates Bortezomib (Velcade) -Induced Neuronal Toxicity in N2a and SHSY5Y Cells
Authors: Park Jinny , Subedi Lalita , Park Su Jung , Lim Oh kyung , Yoo ChanJong , Kim Jong-Suk , Kim Sun Yeou 
Published: October 2019

Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), a potent proteasome inhibitor, is a boronic acid dipeptide that induce cancer cell death. It is an effective drug for both newly diagnosed or relapsed multiple myeloma (MM) patients and is widely used in the treatment of various kinds of lymphomas and other diseases. Peripheral nerve damage is one of the most significant nonhematologic toxicities of bortezomib. The reported incidence of bortezomib-induced peripheral neuropathy (BIPN) ranges from 25 to 75 % . When it occurs, the painful sensory neuropathy can interfere with quality of life (QOL) and with performance of activities of daily living, and it may also adversely affect clinical outcomes by forcing dose modification and/or premature treatment discontinuation. Therefore there are many efforts to improve multiple symptoms associated with BIPN. But there are no reports on amelioration of neurotoxicity which occurred in patients with treatment of bortezomib .Therefore control of this toxicity by the concomitant use of other safe candidates can make it a better option for the cancer therapy with bortezomib.

Glutathione (GSH) is a substance produced naturally by the liver and it is also found in fruits, vegetables, and meats. GSH is an important antioxidant and capable of preventing damage to important cellular components caused by reactive oxygen species (ROS) such as free radicals, peroxides, lipid peroxides, and heavy metals. Several small randomized trials have addressed the protective effect of GSH against chemotherapy induced peripheral neuropathy (CIPN )with a platinum agent .

In this study we observed that treatment of GSH either in the pre-treatment or in the post treatment inhibited the bortezomib -induced neuronal cell death in both mouse neuronal cells (N2a) as well as dopaminergic neuron of human origin (SHSY5Y). Bortezomib treatment at the concentration of 100 and 200 µg/ml significantly increased the cell death with increased lactate dehydrogenase activity (LDH) and increased apoptotic proteins expressions in the 24 h of treatment of both cells. GSH treatment (1 mg/ml) not only inhibited the bortezomib -induced cell death but also inhibited the LDH activity, suggesting that GSH ameliorates bortezomib -induced neuronal toxicity. A clear activation of the autophagy was also observed in the bortezomib treatment that was lowered by the GSH treatment. In addition to this inhibition of the apoptotic proteins specially Cleaved caspase 3 was observed in the neuronal cells and also the increased Bcl2 and NRF2 protein which are responsible for the cell survival was upregulated with GSH treatment suggesting that GSH increase the cell survival against bortezomib -induced neurotoxicity. Inhibition of the cleaved caspase-3, Bax and LC3 protein are prominent in SHSY5Y cells while activation of the BCL2 and NRF2 is more significant in N2a cells. To elucidate the role of GSH in the development and maintenance of bortezomib -induced neurotoxicity, we will additionally assess ROS and antioxidant enzyme activity levels in the cellular system.

This research suggests that GSH ameliorates BIPN and thus can improve the QOL and increase the survival rate of patients treated with bortezomib.

Disclosures

No relevant conflicts of interest to declare.