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. 2025 Jul 10.
doi: 10.1007/s10388-025-01146-3. Online ahead of print.

DCF-resistant ESCC redevelops drug sensitivity when combined with calcium channel blockers due to ER stress response

Wenjie Liao  1 , Satoru Matsuda  2 , Tetsuya Takimoto  3 , Kazumasa Fukuda  1 , Masashi Takeuchi  1 , Hirofumi Kawakubo  1 , Hideyuki Saya  3 , Yuko Kitagawa  1
Affiliations

DCF-resistant ESCC redevelops drug sensitivity when combined with calcium channel blockers due to ER stress response

Wenjie Liao et al. Esophagus. .

Abstract

Background: Esophageal squamous cell carcinoma(ESCC) often develops resistance to standard chemotherapy regimens of docetaxel/cisplatin/5-fluorouracil(DCF) therapy. Strategies to overcome chemoresistance remain a significant clinical challenge.

Methods: DCF-resistant ESCC cell lines were established in the beginning through long-term exposure to chemotherapeutic agents. Gene expression profiles were analyzed via RNA sequencing, and functional assays were conducted to evaluate the impact of various calcium channel blockers(CCBs) on cell viability.

Results: Transcriptomic analysis revealed enrichment of endoplasmic reticulum(ER) stress pathways in DCF-resistant ESCC cells. Among CCBs tested, combined therapy DCF with CCBs restored chemosensitivity.

Conclusion: DCF-resistant ESCC cells were resensitized with combined therapy with DCF and CCBs by enhacing ER stress response. This may provide a potential rationale for repurposing CCBs as adjuvant agents in chemotherapy of ESCC.

Keywords: Calcium channel blockers; Drug evaluation; Drug resistance; Endoplasmic reticulum stress; Esophageal squamous cell carcinoma.

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Conflict of interest statement

Declarations. Conflict of interest: Yuko Kitagawa received research fund from TAIHO Pharmaceutical Co., LTD., CHUGAI Pharmaceutical Co., LTD., Kyouwa Kirin Co., LTD., Nippon Kayaku Co., LTD., DAIICHI SANKYO company, limited and Bristol-Myers Squibb K.K. Hideyuki Saya and Yuko Kitagawa serve as editorial board members of Cancer Science. Ethical statement: This study did not involve human participants or animal subjects and was conducted entirely using established human cancer cell lines in vitro.

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