Cancer

MCI Scientists Find NAD+ Boosting Agent Suppresses Brain Tumor Growth

Mitchell Cancer Institute (MCI) researchers find that elevated NAD+ levels help prevent the growth of chemotherapy-resistant brain tumor cells.

By Daniel R. Miranda, Ph.D.

Key Points: 

  • Combining the NAD+ precursor NRH with chemotherapy enhances the effect of reducing brain tumor cell growth. 
  • NRH raises NAD+ levels in brain tumor cells, suggesting that boosting NAD+ helps prevent tumor growth. 

The most common type of brain tumor is also the most lethal. Deadly tumors called glioblastomas spread rapidly in the brain and are nearly impossible to completely remove. For this reason, these aggressive brain tumors almost always grow back. A chemotherapy drug called temozolomide (TMZ) is used to prevent this regrowth, but some patients are resistant. Now scientists have found that boosting NAD+ may help restore TMZ’s tumor-killing capabilities. 

Researchers from the MCI report in Cancers that resistance to brain tumor treatment can be largely prevented with the help of boosting NAD+ with one of its precursors, dihydronicotinamide riboside (NRH). They show that NRH helps diminish TMZ-resistant glioblastoma cell survival. They also show that NRH increases nicotinamide adenine dinucleotide (NAD+) levels in glioblastoma cells, suggesting that boosting NAD+ is responsible for enhancing tumor suppression.

NRH Aids in Preventing Brain Tumor Cell Growth 

Scientists have been feverishly experimenting with new ways to overcome the low survival rate associated with glioblastomas and TMZ resistance. One solution has been to use drugs called PARG inhibitors (PARGi) in conjunction with TMZ. Li and colleagues previously discovered that NRH enhances PARGi, so they decided to combine PARGi and NRH (with TMZ) to determine if this combination prevents glioblastoma cell growth. They found that TMZ and PARGi inhibit tumor cell growth by less than 40% in TMZ-resistant cells. However, combining TMZ, PARGi, and NRH inhibits tumor cell growth by over 80%, revealing that NRH potentiates the effect of TMZ and PARGi to prevent tumor growth.  

(Li et al., 2022 | Cancers) NRH Enhances Reduction of TMZ Resistant Tumor Cell Growth. Compared to TMZ alone (dark blue), TMZ combined with NRH and PARGi (dark green) strongly inhibits tumor cell growth in TMZ-resistant tumor cells.

Since NRH is a precursor of NAD+, increasing NRH levels should increase NAD+ levels. To check for this, Liu and colleagues measured NAD+ levels in glioblastoma cells after NRH treatment. They found that NAD+ increased in response to NRH in both normal and TMZ-resistant glioblastoma cells, suggesting that the tumor-killing effect of NRH is from boosting NAD+.

(Li et al., 2022 | Cancers) NRH Boosts NAD+ in Brain Tumor Cells. After 8 hours, NAD+ levels are significantly increased in glioblastoma cells, regardless of TMZ resistance.

Is NAD+ Good or Bad for Cancer?

Li and colleagues show that NRH dramatically increases PARGi’s toxicity against glioblastoma cells in the presence of TMZ. However, the Alabama scientists show that TMZ and NRH have no effect on reducing tumor growth unless combined with PARGi. Furthermore, a previous study showed that decreasing NAD+ increased TMZ-resistant glioblastoma growth, suggesting that without PARGi, boosting NAD+ could actually be harmful. This adds to the debate of whether increasing NAD+ levels promotes or hinders cancer growth.

The current research suggests that raising NAD+ levels in cancer cells themselves promotes cancer growth. However, boosting NAD+ can potentially treat other age-related diseases and possibly prevent cancer from developing. Additionally, as demonstrated by the findings of Li and colleagues, combining NAD+ boosters with other molecules like PARGi can enhance the toxicity of chemotherapeutics. This means that while increasing NAD+ in cancer cells may be bad, in combination with other therapies, NAD+ can be good.

Source

Li J, Koczor CA, Saville KM, Hayat F, Beiser A, McClellan S, Migaud ME, Sobol RW. Overcoming Temozolomide Resistance in Glioblastoma via Enhanced NAD+ Bioavailability and Inhibition of Poly-ADP-Ribose Glycohydrolase. Cancers (Basel). 2022 Jul 22;14(15):3572. doi: 10.3390/cancers14153572. PMID: 35892832.

References

Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, Wu Y, Daldrup-Link HE. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol Res. 2021 Sep;171:105780. doi: 10.1016/j.phrs.2021.105780. Epub 2021 Jul 21. PMID: 34302977; PMCID: PMC8384724.

 

Feng J, Yan PF, Zhao HY, Zhang FC, Zhao WH, Feng M. Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway. Biomed Res Int. 2016;2016:1450843. doi: 10.1155/2016/1450843. Epub 2016 Dec 20. PMID: 28097126; PMCID: PMC5206411.

 

Palmer RD, Vaccarezza M. Nicotinamide adenine dinucleotide and the sirtuins caution: Pro-cancer functions. Aging Med (Milton). 2021 Nov 30;4(4):337-344. doi: 10.1002/agm2.12184. PMID: 34964015; PMCID: PMC8711221.

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