Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Abstract

In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

“…Conventional chemo-therapy generates poor patient outcomes due to the heterogeneity of colon cancer, resulting in chemo-/radio-resistance and MDR [158]. In recent decades, numerous attempts have been made to develop targeted strategies for CRC therapy with clinical benefits.…”

Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A

“…Emerging research highlights the role of NO donors in cancer therapy [51,52,53,54]. The most commonly used nitric oxide donors are S-nitrosothiols, clinical nitrovasodilators, and NONOates (diazeniumdiolates).…”

“…The clinical use of commercially available NO donors is limited by the development of tolerance, toxicity issues, and massive release in circulation with undesirable systemic side effects. Clinical and nonclinical studies have tested a number of recently developed NO-drug hybrids, whereby a NO moiety is attached to a known anti-cancer agent, which offers additive anti-tumor effects by each compound while diminishing their respective side effects [51,52,53,54]. Several NO-drug donors are investigated for their effect on various tumors.…”

Senescence and Cancer: Role of Nitric Oxide (NO) in SASP

“…In tumors, high expression of the transcription factor YY1 modulates PD-L1 expression. Treatment with NO donors results in the inhibition of PD-L1 expression via the S-nitrosylation of YY1 [113]. By a nitroproteomic approach, authors uncover a potential mechanism for the ICT where a key protein for T cell activation is nitrated and inactivated by MDSCs.…”