Glutathione-responsive and -exhausting metal nanomedicines for robust synergistic cancer therapy

Abstract

Due to their rapid and uncontrolled proliferation, cancer cells are characterized by overexpression of glutathione (GSH), which impairs reactive oxygen species (ROS)-based therapy and weakens the chemotherapeutic agent-induced toxification. Extensive efforts have been made in the past few years to improve therapeutic outcomes by depleting intracellular GSH. Special focus has been given to the anticancer applications of varieties of metal nanomedicines with GSH responsiveness and exhaustion capacity. In this review, we introduce several GSH-responsive and -exhausting metal nanomedicines that can specifically ablate tumors based on the high concentration of intracellular GSH in cancer cells. These include inorganic nanomaterials, metal-organic frameworks (MOFs), and platinum-based nanomaterials. We then discuss in detail the metal nanomedicines that have been extensively applied in synergistic cancer therapy, including chemotherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), chemodynamic therapy (CDT), ferroptotic therapy, and radiotherapy. Finally, we present the horizons and challenges in the field for future development.

Antiproliferative and Apoptotic Effects of Tempol, Methotrexate, and Their Combinations on the MCF7 Breast Cancer Cell Line

“…Also, TPL's reaction with GSH can facilitate the entry of DOX into the cell by preventing GSH from inhibiting drug transporter proteins. 28 In this way, a decrease in GSH levels can lead to more DOX accumulation in resistant cells. It has been noted that TPL heightens the susceptibility of MCF7 Adr R cells to apoptosis by elevating the expression levels of pro-apoptotic proteins p21 and Bax, while concurrently reducing the expression level of the antiapoptotic protein Bcl-2.…”

“…Decrease in GSH levels and increase in oxidative stress can enhance the efficacy of DOX by inducing ferroptosis in DOX-resistant cells. Also, TPL’s reaction with GSH can facilitate the entry of DOX into the cell by preventing GSH from inhibiting drug transporter proteins . In this way, a decrease in GSH levels can lead to more DOX accumulation in resistant cells.…”

Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy

“…15 Consequently, in order to survive against the treatment with drugs, cancer cells acquire the ability to modulate the redox homeostasis and prevent themselves from undergoing apoptosis if the drugs are incapable of depleting the GSH. 16 A considerable loss of GSH is an indication of regulating the redox signaling events, which trigger the cell death and progression. 17 therapy (PDT), sonodynamic therapy (SDT), chemodynamic therapy (CDT), ferroptosis and chemotherapy.…”

“…Thereby, GSH deteriorates the chemotherapeutic efficiency of the drugs . Consequently, in order to survive against the treatment with drugs, cancer cells acquire the ability to modulate the redox homeostasis and prevent themselves from undergoing apoptosis if the drugs are incapable of depleting the GSH . A considerable loss of GSH is an indication of regulating the redox signaling events, which trigger the cell death and progression .…”

“… 15 Consequently, in order to survive against the treatment with drugs, cancer cells acquire the ability to modulate the redox homeostasis and prevent themselves from undergoing apoptosis if the drugs are incapable of depleting the GSH. 16 A considerable loss of GSH is an indication of regulating the redox signaling events, which trigger the cell death and progression. 17 Plenty of efforts have, therefore, been made over the past few decades to augment the therapeutic efficacy of anticancer drugs by depleting intracellular GSH, as GSH depletion has been validated to recuperate the therapeutic efficacy of ROS-based therapies, viz.…”