Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity.

Shaun W P Rees,Lisa I Pilkington,Christopher S Walker,Tayla A Rees,David Barker,Euphemia Leung

doi:10.3390/ijms222111518

Abstract

Inhibition of phosphatidylcholine-specific phospholipase C (PC-PLC) has previously been shown to be a potential target for novel cancer therapeutics. One downstream consequence of PC-PLC activity is the activation of NF-κB, a nuclear transcription factor responsible for transcribing genes related to oncogenic traits, such as proliferation, angiogenesis, metastasis, and cancer cell survival. Another biological pathway linked to NF-κB is the exogenous delivery of nitric oxide (NO), which decreases NF-κB activity through an apparent negative-feedback loop. In this study, we designed and synthesised 13 novel NO-releasing derivatives of our previously reported class of PC-PLC inhibitors, 2-morpholinobenzoic acids. These molecules contained a secondary benzylamine group, which was readily nitrosylated and subsequently confirmed to release NO in vitro using a DAF-FM fluorescence-based assay. It was then discovered that these NO-releasing derivatives possessed significantly improved anti-proliferative activity in both MDA-MB-231 and HCT116 cancer cell lines compared to their non-nitrosylated parent compounds. These results confirmed that the inclusion of an exogenous NO-releasing functional group onto a known PC-PLC inhibitor enhances anti-proliferative activity and that this relationship can be exploited in order to further improve the anti-proliferative activity of current/future PC-PLC inhibitors.

Highlights

A well-known effect of protein kinase C enzymes (PKC) activity is the activation of transcription factor NF-κB, resulting in transcription of various genes involved in cancer cell survival, proliferation, angiogenesis, and metastasis [5,6,7,8,9,10,11]
Sci. 2021, 22, 11518 known effect of PKC activity is the activation of transcription factor NF-κB, resulting in transcription of various genes involved in cancer cell survival, proliferation, angiogenesis, and metastasis [5,6,7,8,9,10,11]
It can be seen that in general the tested compounds were more effective against MDA-MB-231 than HCT116, which was expected due to the known high expression of phosphatidylcholine-specific phospholipase C (PC-PLC) in the MDA-MB-231 cell line [4]. These results demonstrate that the inclusion of a nitric oxide (NO) releasing motif onto a known PC-PLC inhibitor significantly increased anti-proliferative activity in both triplenegative breast cancer and colon cancer cell lines when compared to their non-nitrosylated counterparts acting through PC-PLC inhibition alone

Summary

Introduction

One downstream consequence of PC-PLC activity is the activation of NF-κB, a nuclear transcription factor responsible for transcribing genes related to oncogenic traits, such as proliferation, angiogenesis, metastasis, and cancer cell survival. Another biological pathway linked to NF-κB is the exogenous delivery of nitric oxide (NO), which decreases NF-κB activity through an apparent negative-feedback loop. It was discovered that these NO-releasing derivatives possessed significantly improved anti-proliferative activity in both MDA-MB-231 and HCT116 cancer cell lines compared to their non-nitrosylated parent compounds These results confirmed that the inclusion of an exogenous NO-releasing functional group onto a known PC-PLC inhibitor enhances anti-proliferative activity and that this relationship can be exploited in order to further improve the anti-proliferative activity of current/future PC-PLC inhibitors.

Objectives

Results

Conclusion