Abstract
The use of chelators for cancer treatment has been an alternative option. Dithiocarbamates have recently attracted considerable attention owning to their diverse biological activities; thus, the preparation of new dithiocarbamate derivatives with improved antitumor activity and selectivity as well as probing the underlying molecular mechanism are required. In this study, di-2-pyridylhydrazone dithiocarbamate S-propionic acid (DpdtpA) and its copper complex were prepared and characterized, and its antiproliferative activity was evaluated. The proliferation inhibition assay showed that DpdtpA exhibited excellent antiproliferative effect in hepatocellular carcinoma (IC50 = 1.3 ± 0.3 μM for HepG2, and 2.5 ± 0.6 μM for Bel-7402). However, in the presence of copper ion, the antiproliferative activity of DpdtpA was dramatically attenuated (20–30 fold) owing to the formation of copper chelate. A preliminarily mechanistic study revealed that reactive oxygen species (ROS) generation mediated the antiproliferative activity of DpdtpA, and accordingly induced apoptosis, DNA cleavage, and autophagy. Surprisingly, the cytotoxicity of DpdtpA copper complex (DpdtpA–Cu) was also involved in ROS generation; however, a paradoxical relation between cellular ROS level and cytotoxicity was observed. Further investigation indicated that DpdtpA could induce cell cycle arrest at the S phase; however, DpdtpA–Cu lacked this effect, which explained the difference in their antiproliferative activity.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and the incidence of HCC is the highest in Asia and Africa
We aimed to target the molecules whose functions depend on the transition metals in the tumor microenvironment, such as matrix metalloproteinases, lysyl oxidase, and vascular endothelial growth factor, which can be used as drug targets to inhibit tumor growth or metastasis
Recent studies revealed that the tumor microenvironment plays a critical role in the cancer growth, metastasis, and treatment responses [29]
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and the incidence of HCC is the highest in Asia and Africa. Tumor metastasis is responsible for approximately 90% of all cancer-related deaths [1]. It has been recognized that a metastatic tumor stems from a primary tumor that acquires an additional ability to invade the extracellular matrix (ECM). In the early expansion of primary tumors, tumor cells secrete signaling molecules to recruit myeloid cells that provide a platform of chemokines, growth factors, and matrix-degrading enzymes [2], which constitute the tumor microenvironment. It has been demonstrated that tumor microenvironment plays an important role in the metastasis process [1,3]; targeting the tumor microenvironment for cancer therapy is an interesting topic for medicinal research [4]
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