Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis

Abstract

Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the anti-proliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC(50) values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.

Process‐relevant concentrations of the leachable bDtBPP impact negatively on CHO cell production characteristics

“…Apoptosis was detected using the Nexin assay which uses the calcium‐dependent phospholipid binding protein, Anexin V/PE which detects the externalization of phosphatidylserine (PS) to the outer surface of the cell membrane during early apoptosis along with 7‐AAD to detect the presence of dead cells. The assay was performed as previously reported in medium containing 5% FCS …”

“…The assay was performed as previously reported in medium containing 5% FCS. 13 Fluorescent-labeled inhibitors of caspases (FLICA) were used to assess the activation of the executioner caspases 3 and 7. 14 After a predefined incubation period in bDtBPP, 3 3 10 5 cells were washed with PBS (1,000 g for 5 min) and resuspended in 100 mL of fresh culture media.…”

Recent developments in the synthesis and biological activity of acridine/acridone analogues

“…4) from the MeOH extract of the fruits of Zanthoxylum zanthoxyloides and Zanthoxylum leprieurii, of which six were new (12, 13, 14, 19, 20 and 21). Acridone molecules (19)(20)(21) that have a tetracyclic acridone structure as their carbon skeleton have been named as zanthacridone. 36 All newly discovered acridones (12, 13, 14, 19, 20 and 21) were tested for antibacterial activity against Bacillus subtilis (MTCC 121), Micrococcus luteus (MTCC 2470), Staphylococcus aureus (MTCC 96), and Pseudomonas aeruginosa (MTCC 741).…”

“…The unique planar ring structure allows acridone derivatives to act as DNA intercalators 19,20 and to inhibit topoisomerase or telomerase enzymes. [21][22][23][24] A variety of acridine/acridone derivatives have been synthesized; analogues such as N-(2-(dimethylamino)ethyl)acridine-4-carboxamide (DACA) (1), [25][26][27] triazoloacridone (C-1305) (2) 28 and amsacrine (m-AMSA) (3) 29 (Fig. 1) have entered clinical studies.…”

Acridone Derivative 8a Induces Oxidative Stress-Mediated Apoptosis in CCRF-CEM Leukemia Cells: Application of Metabolomics in Mechanistic Studies of Antitumor Agents

“…However, the antitumor activity of acridone derivatives has attracted an increasing interest, and a large number of acridone derivatives have been chemically synthesized and tested for antitumor activity. These novel acridone derivatives act as DNA intercalators [8], [9], topoisomerase inhibitors [10], [11] or selective telomeric G-quadruplex DNA ligands [12], [13]. Antitumor activities of acridone derivatives have been traditionally characterized by molecular biological technologies [14], [15], [16], including MTT reduction assay for cellular proliferation, flow cytometry for cellular apoptosis, RT-PCR for gene expression, and Western blot for protein expression.…”