Arsenic-Based Anticancer-Combined Therapy: Novel Mechanism Inducing Apoptosis of Cancer Cells

Abstract

Arsenic, known as both a naturally occurring toxic element and a traditionally used drug, has caught a great deal of attention from worldwide people due to its curable anticancer effect in patients with acute promyelocytic leukemia (APL). Among the arsenicals, arsenic trioxide (ATO) has been the most widely used anticancer drug. Since ATO exerts an anticancer effect by mediating apoptosis, numerous studies have made efforts to uncover the molecular mechanisms by which ATO activates and/or mediates the apoptotic signaling pathway in cancer cells. Recent advances in cancer therapeutics have led to a paradigm shift away from the traditional cytotoxic drugs toward the targeting of proteins closely associated with driving the cancer phenotype. Here, we discuss novel current arsenic-based combination therapies to treat cancer in both clinical and experimental settings. We also discuss the novel molecular mechanism underlying apoptosis induced by the combined therapies.

Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias

“…ATO, as an oxidant factor destroying redox pathways, can act synergistically with oxidants like ascorbate (Noguera et al, 2019). Furthermore, synergistic effect of ATO and bortezomib (BOR) is involved in inhibition of NF‐ k B activity, increased production of ROS, decreased expression of cyclin D1, BCL2 and decreased interaction of Mcl‐1 and Bak in APL and AML (Ota et al, 2018). In spite of the antiproteasomal activity of BOR, ATO in combination with BOR effectively degrades PML‐RARα through autophagy‐dependent degradation.…”

“…In addition, ATO in combination with other drugs such as FLT3‐inhibitor (AG1296), dichloroacetate, azacytidine, rapamicin, aclacinomycin A stimulates apoptosis synergistically in AML. ATO in combination with buthionine sulfoximine (BSO) can effectively induce apoptosis in APL, AML, and other leukemias via the production of intracellular ROS, activation of the oxidative stress‐dependent pathway, depletion of GSH, ROS‐mediated phosphorylation of JNK, and upregulation of death receptor 5 (Ota et al, 2018).…”

Arsenicals Review: Poison vis-a-vis Medicine

“…[3] Many studies are being conducted on the use of arsenicals in cancer treatment. [4] Arsenic has been used as medicine and poison since antiquity. Here an attempt is made to contemplate the journey of arsenicals as medicine-poison-medicine-poison.…”

Biochemical Study in Ehrlich Carcinoma Cells-bearing Mice Treated with Arsenic Trioxide and Cisplatin

“…These imbalances may lead to a proliferation that results in cancer cell death. There is much interest in the potential use of arsenic trioxide (ATO) to treat other malignancies such as gastric cancer [8], neuroblastoma [9], esophageal [10], prostate and ovarian carcinomas [11] . The toxicity of ATO in the heart, liver, kidney, and nervous system [12], particularly cardiac toxicity [13], has limited its clinical utilization.…”