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Adaphostin-induced oxidative stress in oesophageal neuroendocrine carcinoma: a potential therapeutic strategy
Chelsea Penney1, Ann-Katrin Piper2, Jacqueline Holliday2
1School of Science, University of Wollongong, Northfields Ave, North Wollongong, NSW, Australia. cpenney@uow.edu.au.
Abstract:
Advanced oesophageal neuroendocrine carcinoma (ENEC) is a highly aggressive and rare malignancy with poor prognosis. Due to the rarity of this cancer there are currently no standardised treatment regimens for ENEC, and models to study this disease are difficult to obtain. To address this, we screened our established circulating tumour cell line from a patient with metastatic ENEC, termed UWG01CTC, using the LOPAC®1280 drug repurposing library. The redox modulatory agent adaphostin was identified as a potent cytotoxin against UWG01CTC but not non-ENEC cell lines. Secondary adaphostin cell viability screens returned IC50 values of 0.201 ± 0.024 µM confirming the high sensitivity of this ENEC CTC line to the drug. Inclusion of the antioxidant N-acetyl cysteine significantly protected the UWG01CTCs against the cytotoxic effects of adaphostin (IC50 = 0.928 ± 0.425 µM), corroborating a mechanism mediated through the generation of reactive oxygen species (ROS). The expression of DNA damage marker phospho-γH2AX and apoptotic marker cleaved PARP1 were both elevated in cells treated with adaphostin, suggesting that the increased intracellular ROS levels induced by the drug causes downstream DNA damage and ultimately apoptosis. Thus, adaphostin shows promise as a potential new and selective treatment for ENEC.
Insights
Adaphostin effectively targets advanced oesophageal neuroendocrine carcinoma (ENEC) cells by inducing reactive oxygen species (ROS) and DNA damage. This drug shows promise as a selective treatment for this rare and aggressive cancer.
Area of Science:
- Oncology
- Pharmacology
Background:
- Advanced oesophageal neuroendocrine carcinoma (ENEC) is a rare and aggressive malignancy with limited treatment options.
- Studying ENEC is challenging due to the scarcity of disease models.
Purpose of the Study:
- To identify potential therapeutic agents for ENEC using a drug repurposing library.
- To investigate the mechanism of action of identified compounds on ENEC cells.
Main Methods:
- Screening of a circulating tumor cell line (UWG01CTC) from an ENEC patient against the LOPAC®1280 drug library.
- Evaluating the cytotoxic effects of adaphostin and its interaction with N-acetyl cysteine.
- Assessing DNA damage and apoptosis markers (phospho-γH2AX, cleaved PARP1) in treated cells.
Main Results:
- Adaphostin was identified as a potent cytotoxin against the ENEC cell line (IC50 = 0.201 ± 0.024 µM).
- The antioxidant N-acetyl cysteine partially reversed adaphostin's cytotoxicity, indicating a ROS-mediated mechanism.
- Adaphostin treatment increased DNA damage and apoptosis markers in ENEC cells.
Conclusions:
- Adaphostin demonstrates significant and selective cytotoxicity against ENEC cells.
- The mechanism involves the induction of reactive oxygen species (ROS), leading to DNA damage and apoptosis.
- Adaphostin represents a promising candidate for novel ENEC treatment strategies.
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