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Expanding antitumor therapeutic windows by targeting cancer-specific nicotinamide adenine dinucleotide
Gaurab Chakrabarti1, David E Gerber2, David A Boothman1
1Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA ; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA ; Harold C Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA.
Abstract:
Nicotinamide adenine dinucleotide phosphate (NADPH) biogenesis is an essential mechanism by which both normal and cancer cells maintain redox balance. While antitumor approaches to treat cancers through elevated reactive oxygen species (ROS) are not new ideas, depleting specific NADPH-biogenesis pathways that control recovery and repair pathways are novel, viable approaches to enhance cancer therapy. However, to elicit efficacious therapies exploiting NADPH-biogenic pathways, it is crucial to understand and specifically define the roles of NADPH-biogenesis pathways used by cancer cells for survival or recovery from cell stress. It is equally important to select NADPH-biogenic pathways that are expendable or not utilized in normal tissue to avoid unwanted toxicity. Here, we address recent literature that demonstrates specific tumor-selective NADPH-biogenesis pathways that can be exploited using agents that target specific cancer cell pathways normally not utilized in normal cells. Defining NADPH-biogenesis profiles of specific cancer-types should enable novel strategies to exploit these therapeutic windows for increased efficacy against recalcitrant neoplastic disease, such as pancreatic cancers. Accomplishing the goal of using ROS as a weapon against cancer cells will also require agents, such as NQO1 bioactivatable drugs, that selectively induce elevated ROS levels in cancer cells, while normal cells are protected.
Insights
Targeting cancer cell Nicotinamide adenine dinucleotide phosphate (NADPH) production offers a novel therapy. Exploiting tumor-specific NADPH pathways spares normal cells, enhancing cancer treatment efficacy and reducing toxicity.
Area of Science:
- Biochemistry
- Oncology
- Cellular Biology
Background:
- Nicotinamide adenine dinucleotide phosphate (NADPH) biogenesis is crucial for cellular redox balance in both normal and cancer cells.
- Elevating reactive oxygen species (ROS) is a known antitumor strategy, but novel approaches focus on depleting cancer-specific NADPH pathways.
Purpose of the Study:
- To review literature on exploiting tumor-selective NADPH-biogenesis pathways for enhanced cancer therapy.
- To identify NADPH pathways that are essential for cancer cell survival but not for normal cells, minimizing toxicity.
Main Methods:
- Literature review of studies investigating NADPH-biogenesis pathways in various cancer types.
- Analysis of selective targeting agents, such as NQO1 bioactivatable drugs, for ROS induction in cancer cells.
Main Results:
- Specific tumor-selective NADPH-biogenesis pathways can be targeted to enhance cancer therapy.
- Defining cancer-type-specific NADPH profiles can reveal exploitable therapeutic windows.
- Agents like NQO1 bioactivatable drugs can selectively increase ROS in cancer cells, protecting normal cells.
Conclusions:
- Targeting cancer-specific NADPH pathways presents a viable strategy to enhance cancer treatment efficacy.
- Understanding NADPH biogenesis profiles is key to developing novel therapeutic strategies against recalcitrant cancers like pancreatic cancer.
- Selective ROS induction in cancer cells, while sparing normal cells, is crucial for effective and safe antitumor therapies.
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