High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines

Xiaochang Shen; Jiandong Wang; Boer Deng; Shuning Chen; Catherine John; Ziyi Zhao; Nikita Sinha; Jennifer Haag; Wenchuan Sun; Weimin Kong; Ivan Spasojevic; Ines Batinic-Haberle; Angeles Alvarez Secord; Chunxiao Zhou; Victoria L Bae-Jump

doi:10.1016/j.ygyno.2024.03.021

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines

Gynecol Oncol. 2024 Mar 30:183:93-102. doi: 10.1016/j.ygyno.2024.03.021. Online ahead of print.

Authors

Affiliations

¹ Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, PR China; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100006, PR China.
³ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Medicine, Duke University School of Medicine, and PK/PD Core Laboratory, Duke Cancer Institute, Durham, NC 27710, USA.
⁵ Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA.
⁶ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University, Durham, NC 27710, USA.
⁷ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: czhou@med.unc.edu.
⁸ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: victoria_baejump@med.unc.edu.

PMID: 38555710
DOI: 10.1016/j.ygyno.2024.03.021

Abstract

Objective: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells.

Methods: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting.

Results: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells.

Conclusions: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Keywords: Ascorbate; Carboplatin; Cell proliferation; Invasion; Synergy; Uterine serous carcinoma.