Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma

Abstract

Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed. These molecules when combined with TMZ show major tumor cytotoxicity that is effective in suppressing growth of cancer cells in both drug sensitive and resistant sub-populations of a tumor. In this study a novel mathematical model has been developed to explore the various drug combinations that may be useful for the treatment of resistant Glioma and show that the combinations of TMZ and Acridone derivatives have a synergistic effect. Also, acute toxicity studies of all three acridone derivatives were carried out for 14 days and were found safe for oral administration of 400 mg/kg body weight on albino Wistar rats. Molecular Docking studies of acridone derivatives with P-glycoprotein (P-gp), multiple resistant protein (MRP), and O6-methylguanine-DNA methyltransferase (MGMT) revealed different binding affinities to the transporters contributing to drug resistance. It is observed that while the Acridone derivatives bind with these drug resistance causing proteins, the TMZ can produce its cytotoxicity at a much lower concentration leading to the synergistic effect. The in silico analysis corroborate well with our experimental findings using TMZ resistant (T-98) and drug sensitive (U-87) Glioma cell lines and we propose three novel drug combinations (TMZ with AC2, AC7, and AC26) and dosages that show high synergy, high selectivity and low collateral toxicity for the use in the treatment of drug resistant Glioma, which could be future drugs in the treatment of Glioblastoma.

Acridine–O6-benzylguanine hybrids: Synthesis, DNA binding, MGMT inhibition and antiproliferative activity

“…This effect is in line with the recently described activity of structurally related acridones to potentiate the cytotoxic effects of TMZ [76]. While the detailed studies of the mechanism of intrinsic cytotoxic effects of this compound are outside the scope of this work, this unexpected property represents a novel addition to a multitude of biological effects of acridine derivatives.…”

“…Interestingly, during the preparation of this manuscript, MGMT binding of structurally related acridone derivatives was suggested on the basis of molecular docking experiments [76]; moreover, inhibition of MGMT activity by other polyaromatic compounds was previously documented [77]. Inactivation of MGMT by the acridine residue can also explain the inhibitory effect of the hybrids 13 and 14 that do not contain a BG moiety, as well as an increase of the inhibitory activity of all hybrids observed upon pre-incubations of compounds with the enzyme prior to addition of the target.…”

New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4

“…The sequential application of several drugs, used for different purposes, can have an impact on the cells at different extent; for instance, the co‐administration of a PADI inhibitor and an androgen receptor signal transduction inhibitor hampered tumor growth in prostate cancer and cell proliferation (Wang et al, 2017 ). In that way, the use of TMZ in combination with other drugs can increase its cytotoxicity at a much lower concentration than when used in isolation (Chakravarty et al, 2021 ). Therefore, we speculated that the treatment of GBM tumor cells by TMZ could be also enhanced by the presence of GSK484.…”

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review)

“…To improve the bioavailability of active drugs by preventing rapid degradation or drug resistance, other strategies have been used in addition to nanotechnology, such as synergistic substances or tumour-targeting peptides. TMZ may be either administered alone, or in combination with radiotherapy or with other active substances, including acridone derivatives (33), chlorotoxin (28), the bromodomain inhibitor JQ1 (27) or doxorubicin (18), with the aim of improving the treatment outcomes.…”

“…A synergistic approach has been studied using acridone derivatives combined with TMZ. This combination was found to exert major tumour cytotoxic effects, effectively suppressing malignant cell proliferation in both sensitive and resistant tumour cell subpopulations (33).…”