# Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies
## 6 Is Increased NAD+ Tumorigenic?  
There are a few reports of genotoxicity of nicotinic acid, while NAM and NR were not found to be genotoxic [106]. Nicotinamide, NR, and NMN were also not found to  
\begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline \multirow{2}{*}{\begin{tabular}{c} **NAD+** \\ **Precursor** \\ \end{tabular} } & \multirow{2}{*}{\begin{tabular}{c} **Not** \\ **Recruiting** \\ \end{tabular} } & \multicolumn{4}{c}{**Number of Studies**} & \multicolumn{1}{c}{\multirow{2}{*}{**Suspended**}} & \multicolumn{1}{c}{\multirow{2}{*}{\
\begin{tabular}{c} **Unknown** \\ **Status** \\ \end{tabular} }} \\ \cline{2-3} \cline{5-7}  &
\begin{tabular}{c} **Not** \\ **Recruiting** \\ \end{tabular} & & & & & & & \\ \hline
**NR** & 3 & 10 & 4 & 1 & 24 & 2 & 8 \\
**NMN** & 0 & 5 & 2 & 0 & 7 & 0 & 0 \\
**Niccin** & 22 & 110 & 24 & 39 & 357 & 5 & 47 \\
**Tryptophan** & 16 & 57 & 14 & 21 & 131 & 0 & 38 \\ \hline \hline \end{tabular}
\end{table}
Table 1: Information on clinical trials regarding NAD+ precursors: NR, NMN, niacin (nicotinic acid and niacinamide/nicotinamide) and tryptophan.  
be directly carcinogenic [23; 127]. No evidence was found that treatment with NR or NMN for a prolonged period stimulated tumor development in animals [17; 105] although further studies are warranted since ingestion of NAD+ boosters results in elevated NAD+ levels that could indirectly influence tumorigenesis. Indeed, levels of NAD+ are a crucial protective factor in early carcinogenesis and could later become a detrimental factor in the phases of cancer development and promotion. Specifically, maintenance of adequate NAD+ levels regulates redox homeostasis and mitochondrial metabolism, which are predisposed conditions for genome integrity and prevention of tumorigenesis [128]. However, in the phase of cancer progression and treatment, elevated NAD+ levels may have deleterious effects on the process of malignancy by promoting cell survival, encouraging growth, increasing resistance to radio- and chemotherapy, and promoting inflammation (reviewed in [24; 129]) and stimulation of angiogenesis [130]. Although increased NAD+ levels can induce resistance to radiotherapy, nicotinamide (as a radiosensitizer) is administered as a strategy to improve the radio-sensitivity [131].  
In contrast, it is feasible that restoration of NAD+ in the early stages of the carcinogenic process induces cellular repair and adaptive stress responses and regulates cell cycle arrest and apoptotic clearance of damaged cells, thus preventing or reversing the malignant phenotype (reviewed in [24]). For example, the potential pro-tumorigenic side effects of NAD+ precursor NMN were discussed by [PERSON] et al. (2019): NMN intake by mice increased NAD+ levels, which influenced the secretory activity of senescent cells to promote tumor progression of pancreatic and ovarian cancers [132]. In contrast, restoring NAD+ pools with NR prevented DNA damage and hepatocellular carcinoma formation in a mouse model of a liver cancer [27].  
Increased NAMPT activity was observed in several human cancers [133], and NAMPT inhibition by drugs is promising as a cancer treatment. For example, FK866 has anticancer effect. It is an inhibitor of nicotinamide-recycling enzyme (NAMPT/PBEF) that catalyzes the rate-limiting step of NAD+ synthesis [134], resulting in apoptosis induction in a tumor due to NAD+ depletion [135]. Activity of sirtuins and PARPs is modulated by NAD+ levels. They have both procancer and anticancer effects [136; 137; 138; 139; 140; 141]. Therefore, their role in cancer prevention and promotion must be fully elucidated in future studies. In conclusion, severe deficiency of NAD+ stops cancer growth, whereas an increase in NAD+ level might promote cellular NAD+ anabolism and accelerate tumor growth.