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

Wenjie Liao; Satoru Matsuda; Tetsuya Takimoto; Kazumasa Fukuda; Masashi Takeuchi; Hirofumi Kawakubo; Hideyuki Saya; Yuko Kitagawa

doi:10.1007/s10388-025-01146-3

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

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

Oncology Innovation Center

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Background: Esophageal squamous cell carcinoma(ESCC) often develops resistance to standard chemotherapy regimens ofdocetaxel/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 ofvarious 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 stressresponse. This may provide a potential rationale for repurposing CCBs as adjuvant agents in chemotherapy of ESCC.

Original language	English
Pages (from-to)	631-640
Number of pages	10
Journal	Esophagus
Volume	22
Issue number	4
DOIs	https://doi.org/10.1007/s10388-025-01146-3
Publication status	Published - 10-2025

All Science Journal Classification (ASJC) codes

Gastroenterology

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10.1007/s10388-025-01146-3

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

abstract = "Background: Esophageal squamous cell carcinoma(ESCC) often develops resistance to standard chemotherapy regimens ofdocetaxel/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 ofvarious 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 stressresponse. 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",

author = "Wenjie Liao and Satoru Matsuda and Tetsuya Takimoto and Kazumasa Fukuda and Masashi Takeuchi and Hirofumi Kawakubo and Hideyuki Saya and Yuko Kitagawa",

note = "Publisher Copyright: {\textcopyright} The Author(s) under exclusive licence to The Japan Esophageal Society 2025.",

year = "2025",

month = oct,

doi = "10.1007/s10388-025-01146-3",

language = "English",

volume = "22",

pages = "631--640",

journal = "Esophagus",

issn = "1612-9059",

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number = "4",

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TY - JOUR

T1 - DCF-resistant ESCC redevelops drug sensitivity when combined with calcium channel blockers due to ER stress response

AU - Liao, Wenjie

AU - Matsuda, Satoru

AU - Takimoto, Tetsuya

AU - Fukuda, Kazumasa

AU - Takeuchi, Masashi

AU - Kawakubo, Hirofumi

AU - Saya, Hideyuki

AU - Kitagawa, Yuko

N1 - Publisher Copyright: © The Author(s) under exclusive licence to The Japan Esophageal Society 2025.

PY - 2025/10

Y1 - 2025/10

N2 - Background: Esophageal squamous cell carcinoma(ESCC) often develops resistance to standard chemotherapy regimens ofdocetaxel/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 ofvarious 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 stressresponse. This may provide a potential rationale for repurposing CCBs as adjuvant agents in chemotherapy of ESCC.

AB - Background: Esophageal squamous cell carcinoma(ESCC) often develops resistance to standard chemotherapy regimens ofdocetaxel/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 ofvarious 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 stressresponse. This may provide a potential rationale for repurposing CCBs as adjuvant agents in chemotherapy of ESCC.

KW - Calcium channel blockers

KW - Drug evaluation

KW - Drug resistance

KW - Endoplasmic reticulum stress

KW - Esophageal squamous cell carcinoma

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UR - https://www.scopus.com/pages/publications/105010476479#tab=citedBy

U2 - 10.1007/s10388-025-01146-3

DO - 10.1007/s10388-025-01146-3

M3 - Article

C2 - 40637990

AN - SCOPUS:105010476479

SN - 1612-9059

VL - 22

SP - 631

EP - 640

JO - Esophagus

JF - Esophagus

IS - 4

ER -

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

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