Epigenetic Activity of Cancer Therapy Drugs Revealed by HeLa TI Cell-Based Assay

TL;DR

This study shows that many cancer drugs affect the epigenetic state of cancer cells, which could improve treatment strategies and help overcome drug resistance.

Contribution

The study reveals the epigenetic activity of 15 widely used cancer therapy drugs using a HeLa TI cell-based assay.

Findings

Epigenetic activity was observed in 15 drugs with diverse mechanisms, including chemotherapeutics, targeted agents, and corticosteroids.

Drugs like chlorambucil, cisplatin, and docetaxel significantly increased GFP-positive cells, indicating epigenetic reactivation.

The findings suggest that epigenetic modulation by these drugs may enhance treatment efficacy and combination therapies.

Abstract

Background/Objectives: The aberrant epigenetic landscape of cancer cells has attracted wide attention, motivating the search for new epigenetically active drugs both for anticancer therapy and for overcoming the drug resistance promoted by epigenetic changes. The use of epi-drugs in cancer therapy requires consideration of the influence of applied treatment on epigenetic regulation of gene expression. Therefore, it is reasonable to screen epigenetically active compounds among the drugs widely used in clinical oncology. Methods: We applied the HeLa TI cell-based assay to analyze the epigenetic activity of 40 drugs including 22 chemotherapeutic, 2 immunotherapeutic, 13 targeted, and 3 palliative agents. Reactivation of the epigenetically silenced GFP reporter gene integrated into the genome of HeLa TI cells was assessed using flow cytometry. Results: Statistically significant increases in the proportions of GFP-positive cells were demonstrated for the alkylating agent chlorambucil; the antimetabolites cytarabine, fluorouracil, gemcitabine, and pemetrexed; the platinum-based compounds cisplatin, and oxaliplatin; the topoisomerase inhibitor topotecan; and the antimicrotubule agents docetaxel, vincristine, and eribulin. Epigenetic activity was also detected for the targeted-therapy agents AZD8055, wortmannin, and cetuximab, as well as for the corticosteroid dexamethasone. Thus, epigenetic activity was revealed for 15 drugs widely used in cancer therapy, which possess different modes of action. Conclusions: Our findings show that many anticancer therapy agents modulate the epigenetic landscape of cancer cells, providing a rationale for expanding their therapeutic applications and enhancing the efficacy of combination strategies by overcoming epigenetically driven chemoresistance.

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