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Caspase-Independent Cell Death Induced by a Nitric Oxide Donor Derived from Valproic Acid in Human Pancreatic Cancer

Koji Nishi1,2, Ayaka Ueda1, Takuro Beppu1

  • 1Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.

Biological & Pharmaceutical Bulletin
|March 4, 2026
PubMed

Insights

A novel valproic acid-derived nitric oxide (NO) donor, NVA, effectively reduces pancreatic cancer cell viability. NVA induces cell death through a NO-dependent, caspase-independent pathway, distinct from apoptosis.

Area of Science:

  • Oncology
  • Biochemistry
  • Pharmacology

Background:

  • Nitric oxide (NO) has complex roles in tumor biology, affecting blood flow and cell death.
  • Developing targeted cancer therapies remains a critical challenge in oncology.

Purpose of the Study:

  • To synthesize and characterize a novel nitric oxide (NO) donor derived from valproic acid (VA).
  • To investigate the cytotoxic mechanism of this novel NO donor (NVA) in human pancreatic cancer cells.

Main Methods:

  • Synthesis of a novel valproic acid-derived nitric oxide donor (NVA).
  • Assessment of NVA's nitric oxide release kinetics.
  • Evaluation of NVA's effect on pancreatic cancer cell viability (BxPC-3).
  • Flow cytometry and Western blotting to elucidate the cell death pathway, including caspase activity.

Main Results:

  • NVA demonstrated rapid initial nitric oxide (NO) release followed by stabilization.
  • NVA significantly reduced pancreatic cancer cell viability, while valproic acid (VA) alone had minimal effect.
  • NVA-induced cell death was confirmed to be NO-dependent and caspase-independent, bypassing classical apoptosis.

Conclusions:

  • NVA represents a novel therapeutic strategy for pancreatic cancer, inducing cell death via a non-apoptotic pathway.
  • Valproic acid-based NO donors show potential as effective antitumor agents against pancreatic cancer.
Keywords:
apoptosiscaspase-independent cell deathnitric oxide donorpancreatic cancervalproic acid

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