Can Nitric Oxide-Based Therapy Be Improved for the Treatment of Cancers? - A Perspective

Sep 24, 2026

Nitric oxide (NO) shows cytotoxicity toward cancer cells at high concentrations and may support cancer treatment, prompting development of NO-donors to deliver NO to tumors. NO can also sensitize clinically active anticancer drugs and reverse multi-drug resistance in tumor cells expressing ATP-binding cassette transporters. Effective cancer therapy requires precise tumor delivery while minimizing adverse toxicity. This prospective study surveys strategies for delivering NO-donors to achieve cytotoxic tumor concentrations with fewer reactions.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

NO as a promising anticancer therapeutic

Challenges in selective NO delivery

Strategies using synthetic NO donors

Perspective Can Nitric Oxide-Based Therapy Be Improved for the Treatment of Cancers? A Perspective Birandra K. Sinha Citation: Sinha, B.K. Can Nitric Oxide-Based Therapy Be Improved for the Treatment of Cancers? A Perspective. Int. J. Mol. Sci. 2023, 24, 13611. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms241713611 Academic Editor: Nam Deuk Kim Received: 7 August 2023 Revised: 30 August 2023 Accepted: 31 August 2023 Published: 2 September 2023 Copyright: © 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA; [sinha1@niehs.nih.gov](sinha1@niehs.nih.gov); Tel.: +1-984-287-3382 Abstract: Since the early observations that nitric oxide (􀀏 NO) at high concentrations is cytotoxic to cancer cells and that it may play an important role in the treatment of human cancers, a signiﬁcant number of compounds (NO-donors) have been prepared to deliver 􀀏 NO to tumors. 􀀏 NO also sensitizes various clinically active anticancer drugs and has been shown to induce the reversal of multi-drug resistance in tumor cells expressing ATP-binding cassette-transporter proteins. For the successful treatment of cancers, 􀀏 NO needs to be delivered precisely to tumors, and its adverse toxicity must be limited. Like other chemotherapeutics, the precise delivery of drugs has been a problem and various attempts have been made, such as the encapsulation of drugs in lipid polymers, to overcome this. This prospective study examines the use of various strategies for delivering 􀀏 NO (using NO-donors) for the treatment of cancers. Finding and utilizing such a delivery system is an important step in delivering cytotoxic concentrations of 􀀏 NO to tumors without adverse reactions, leading to a successful clinical outcome for patient management. Keywords: nitric oxide; cancer; drug delivery; liposomes 1. Introduction The growth and survival of cancer cells in vivo is complex and involves many pathways. Tumors, in general, are heterogeneous, containing many different types of cells, including cancer stem cells, which are resistant to therapy. Furthermore, cancer cells develop resistance during therapy. Therefore, successful cancer treatment in the clinic has been difﬁcult. Nitric oxide (􀀏 NO) has emerged as a promising therapeutic for the treatment of many human cancers [1–3] . 􀀏 NO, a free radical produced endogenously by nitric oxide synthase (NOS), has a relatively short half-life (2.0–0.18 s) under physiological conditions [4]; thus, it is difﬁcult to deliver it selectively to cellular targets. As a free radical,􀀏 NO chemically reacts with cellular protein-SH and many other free radicals in biological environments, producing adverse reactions [5] . Additionally, different concentrations of 􀀏 NO have different physiological effects: at a low concentration, 􀀏 NO can be used to regulate vasodilation, nerve transmission, anti-inﬂammatory responses, and antioxidant responses, and it also promotes tumor growth [6–8] . In contrast, at high concentrations,􀀏 NO inhibits tumor growth and enhances the apoptosis/ferroptosis of tumor cells via the formation of both reactive oxygen and reactive nitrogen species [8] . Because of this double-edged nature of 􀀏 NO in the regulation of physiological processes, 􀀏 NO must be delivered selectively to its target sites to limit off-target adverse effects. Various molecular structures and chemical materials have been developed to exogenously deliver 􀀏 NO using synthetic NO donors (e.g., S-nitrosothiols (RSNOs), Ndiazeniumdiolates

FAQs

Why is nitric oxide considered a promising therapy for many cancers?

Nitric oxide can be cytotoxic to cancer cells at high concentrations and is also implicated in therapeutic effects in human cancers. It may support treatment by modulating tumor biology and cellular processes.

What makes selective delivery of nitric oxide difficult in vivo?

Nitric oxide has a short physiological half-life and reacts with cellular components and other free radicals, which can produce adverse reactions. Different NO concentrations also lead to different physiological outcomes, increasing the need for site-selective delivery.

What is the goal of using NO-donors in cancer therapy?

NO-donors are designed to deliver NO precisely to tumors so cytotoxic concentrations can be reached while adverse toxicity is limited. The document emphasizes delivery systems and strategies to improve targeting and therapeutic outcomes.

Sep 24, 2026

Uploaded by Chumphorn