Abstract
Anthraquinone derivatives exhibit various biological activities, e.g., antifungal, antibacterial and in vitro antiviral activities. They are naturally produced in many fungal and plant families such as Rhamnaceae or Fabaceae. Furthermore, they were found to have anticancer activity, exemplified by mitoxantrone and pixantrone, and many are well known redox-active compounds. In this study, various nature inspired synthetic anthraquinone derivatives were tested against colon, prostate, liver and cervical cancer cell lines. Most of the compounds exhibit anticancer effects against all cell lines, therefore the compounds were further studied to determine their IC50-values. Of these compounds, 1,4-bis(benzyloxy)-2,3-bis(hydroxymethyl)anthracene-9,10-dione (4) exhibited the highest cytotoxicity against PC3 cells and was chosen for a deeper look into its mechanism of action. Based on flow cytometry, the compound was proven to induce apoptosis through the activation of caspases and to demolish the ROS/RNS and NO equilibrium in the PC3 cell line. It trapped cells in the G2/M phase. Western blotting was performed for several proteins related to the effects observed. Compound 4 enhanced the production of PARP and caspase-3. Moreover, it activated the conversion of LC3A/B-I to LC3A/B-II showing that also autophagy plays a role in its mechanism of action, and it caused the phosphorylation of p70 s6 kinase.
Highlights
Cancer is one of the most common and threatening human diseases
It activated the conversion of LC3A/B-I to LC3A/B-II showing that autophagy plays a role in its mechanism of action, and it caused the phosphorylation of p70 s6 kinase
Autophagy counteracts the action of apoptosis through the elimination of the damaged organelles and proteins leading to the production of energy which could be utilized for the survival of the cell [10]
Summary
Cancer is one of the most common and threatening human diseases. In 2018, it was estimated that 18.1 million persons were diagnosed with cancer worldwide. Chemotherapy is considered the mainstay of cancer treatment combined with either radiotherapy or surgery This therapy includes various groups of agents, each has a specific mode of action such as alkylating agents, metal-based agents, antimetabolites, topoisomerase inhibitors and tubulin binding agents, etc. Anthraquinone derivatives are a group of aromatic compounds that have anthraquinone (Figure 1a) as main structural core They are widely used nowadays in the dye indus3troyf [1162], paper industry and for the synthesis of H2O2 [13]. To determine the cytotoxic effect of the anthraquinone derivatives, several cancer cell lines of different origins were used. Colon, cervix and liver cancer cell lines (PC3, HT-29, HeLa and HepG2; respectively) were included. These cell lines were from the cell line stock of the Leibniz Institute of Plant Biochemistry. Cells were seeded at 1.5 × 103 cells/well in 96-well plates for viability determination and 1 × 105 cells/well in 6-well plates for flow cytometry and western blotting
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