Diphenyl Ditelluride‐Induced Cell Cycle Arrest and Apoptosis: A Relation with Topoisomerase I Inhibition

Abstract

The diphenyl ditelluride (DPDT) is a prototype for the development of new biologically active molecules. In previous studies, DPDT showed an elevated cytotoxicity in Chinese hamster fibroblast (V79) cells but the mechanisms for reduction of cell viability still remain unknown. DPDT showed mutagenic properties by induction of frameshift mutations in bacterium Salmonella typhimurium and yeast Saccharomyces cerevisiae. This organotelluride also induced DNA strand breaks in V79 cells. In this work, we investigated the mechanism of DPDT cytotoxicity by evaluating the effects of this compound on cell cycle progression, apoptosis induction and topoisomerase I inhibition. Significant decrease of V79 cell viability after DPDT treatment was revealed by MTT assay. Morphological analysis showed induction of apoptosis and necrosis by DPDT in V79 cells. An increase of caspase 3/7 activity confirmed apoptosis induction. The cell cycle analysis showed an increase in the percentage of V79 cells in S phase and sub-G1 phase. The yeast strain deficient in topoisomerase I (Topo I) showed higher tolerance to DPDT compared with the isogenic wild-type strain, suggesting that the interaction with this enzyme could be involved in DPDT toxicity. The sensitivity to DPDT found in top3Δ strain indicates that yeast topoisomerase 3 (Top3p) could participate in the repair of DNA lesions induced by the DPDT. We also demonstrated that DPDT inhibits human DNA topoisomerase I (Topo I) activity by DNA relaxation assay. Therefore, our results suggest that the DPDT-induced cell cycle arrest and reduction in cell viability could be attributed to interaction with topoisomerase I enzyme.

AMPK‐mTOR‐ULK1 axis activation‐dependent autophagy promotes hydroxycamptothecin‐induced apoptosis in human bladder cancer cells

“…Once severe DNA damage occurred, various biological processes might be triggered by activating signaling pathways, including programmed cell apoptosis, AMPK/mTOR‐dependent autophagy and cell‐cycle arrest (Czarny, Pawlowska, Bialkowska‐Warzecha, Kaarniranta, & Blasiak, ; Jorge et al, ; D. Zhang et al, ). On the basis of the previous studies and the targeting characteristic of HCPT, we supposed that HCPT might induce apoptosis and autophagy via DNA topoisomerase I inhibition and irreversible DNA damage.…”

“…Once severe DNA damage occurred, various biological processes might be triggered by activating signaling pathways, including programmed cell apoptosis, AMPK/mTOR-dependent autophagy and cell-cycle arrest (Czarny, Pawlowska, Bialkowska-Warzecha, Kaarniranta, & Blasiak, 2015;Jorge et al, 2015;D. Zhang et al, 2015).…”

Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties

“…Cell death induction mechanisms are diverse, and it is broadly recognized that the effectiveness of Te compounds as anticancer agents is dependent on their chemical form and dose as well as on their redox state and the experimental model used [23, 33, 44, 45]. There is emerging evidence that cell death induced by Te compounds is associated with ROS formation, cell cycle arrest, induction of programmed cell death, and immunomodulatory effects [33].…”

“…There is emerging evidence that cell death induced by Te compounds is associated with ROS formation, cell cycle arrest, induction of programmed cell death, and immunomodulatory effects [33]. Moreover, Te compounds may induce cell death by distinct pathways, either caspase-dependent or caspase-independent, depending on the chemical form and system studied [22, 23, 44]. Some mechanisms and actions of DPDT and other Te compounds are discussed below.…”

“…In the present review, we emphasize the biological activities of an OT compound, diphenyl ditelluride (DPDT) (Figure 1), aiming to argue and discuss its contrasting antioxidant [21], cytotoxic [22], and antiproliferative [20, 23] effects.…”