Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer

Figures & data

Figure 1. Functional interactions among Bcl-2 family members.

Inhibitory interactions among pro-survival members (dark grey boxes), and strong (dark grey ovals) versus weak (light grey ovals) BH3-only members. Stimulatory (arrow) and inhibitory (blockline) interactions among pro-survival Bcl-2 members, BAX/BAK1, and strong BH3-only members. NOXA is tentatively represented as activator of BAK and BAX based on Refs. 20–23.Figure compiled and adapted from information and similar schemes represented in Refs [8,9,18,20].

Figure 2. Protein regulation of NOXA and MCL1, and drugs that target these aspects.

Schematic overview of current knowledge of protein regulation of NOXA and MCL1 via the (de)ubiquitination machinery. Drugs with proven or clearly expected clinical potential are indicated by boxes at the steps they target. See main text for details. Ub = Ubiquitin, K11, K48 denote lysine11 or Lys48 linkage in ubiquitin chains.

Figure 3. Signaling and cell stress pathways that impact on NOXA gene expression.

Schematic depiction of the NOXA locus and promoter region. Transcription factors and cell stress pathways implicated in the induction of NOXA mRNA expression are shown above. Epigenetic factors and regulators are shown below. Arrow indicates transcription start site (TSS). See text for detailed description. H3K27Me3 = Histone H3 lysine27 trimethylation.

Table 1. Ordering of cell stress pathways that affect Noxa level or function, with potential drugs and stage of clinical development indicated.

Category (see text)	Pathway	Mechanistic link to Noxa	Reference(s)	Potential drug(s)	Clinical stage
1.	Autophagy	Tentative	[97,98]	NA	Preclinical
				HA14-1	Preclinical
				Carbamazepine	FDA approved
				Clonidine	FDA approved
				Metformin Rilmenidine	FDA approved
					FDA approved
	Metabolism	Probable but not clear how	[91]	AICAR	Phase I/II trial
2.	ROS	Established but not clear how	[56,144,145]	Bortezomib	FDA approved
				Cisplatin	FDA approved
				Beta-lapachone (ARQ-761)	Phase I/II trial
				Elesclomol	Phase III trial
	Cell cycle stress	Probable – various transcription factors proposed	[52,53]	Taxol	FDA approved
				palbociclib	FDA approved
	Epigenetics	Probable – various transcription factors proposed	[60,61]	HDACs – Vorinostat	FDA approved
				DNMT inhibitors (5-azacitidine, decitabine)	FDA approved
				Bromodomain inhibitors (JQ1)	Phase I/II trials
3.	Hypoxia	Established – Hif1a binding site in Noxa promoter known	[63]	n.a.	n.a.
	ER stress	Established via Noxa siRNA	[68–75,82]	Bortezomib	FDA approved
				Carfilzomib	FDA approved
				Gossypol (AT-101)	Phase I/II trial
				Apogossypol	Preclinical
				HA14-1	Preclinical
				Pemetrexed	FDA approved
	Protein turnover	Firmly established	[41–43,76–79,82]	Bortezomib	FDA approved
				Carfilzomib	FDA approved
				MLN4924 (Pevonedistat)	Phase I/II trial
4.	Bcl-2 family function	Firmly established – Noxa binding to Mcl-1	[108]	S63845	Preclinical

n.a. = not applicable.

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