T267- Synergistic Antitumor Effect of a NAMPT Inhibitor and a NAD Kinase Inhibitor in Mutant IDHI Cancers (Alvinsyah Adhityo Pramono; Joseph R. Bertino; Keri Lestari; Herry Herman; Debabrata Baneriee; Sharon R. Pine; Anas Subarnas; Tri Hanggono Achmad; Rizky Abdulah)

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T267- Synergistic Antitumor Effect of a NAMPT Inhibitor and a NAD Kinase Inhibitor in Mutant IDHI Cancers (Alvinsyah Adhityo Pramono; Joseph R. Bertino; Keri Lestari; Herry Herman; Debabrata Baneriee; Sharon R. Pine; Anas Subarnas; Tri Hanggono Achmad; Rizky Abdulah)

NAD(H) and NADPH are important cofactors in cellular metabolism. These molecules protect cancer cells from detrimental effect of ROS generated in actively proliferating cancer cells. NAD is generated through three biosynthetic pathways, i.e., nicotinic acid pathway, de novo synthesis pathway, and NAD salvage pathway. In order to efficiently reduce NAD pools and to avoid redundancy, we investigated mutant isocitrate dehydrogenase 1/2 (mIDH1/2) cancers that lack the nicotinic acid pathway. Mutant IDH1/2 protein converts α-ketoglutarate into D-2-hydroxyglutarate (D-2HG), an oncometabolite that accelerates the tumorigenesis process and inhibits NAPRT in the nicotinic acid pathway. STF-118804, a NAMPT inhibitor, and Thionicotinamide (ThioNa), a NADK inhibitor, were tested for cytotoxicity in mIDH1 cancer cell lines C85, HCT16, HCT8, and HT1080. Results showed that STF-118804 sensitized all cell lines with the highest and the lowest IC50= 70 μM and 150nM. ThioNa also exhibited cytotoxicity ranging from 25μM-150μM. the combination of both drugs achieved appreciable synergistic activity in mIDH1 cancers with combination index (CI) value at ED50 ranging from 0.30-0.53. Metabolomics study has showed that the drug combination significantly decreases 2-HG, NAD, NADPH, ATP, isocitrate, and α-ketoglutarate compared to the control group. Thus, the (iii)
combination of both NAMPT inhibitor and NADK inhibitor might be a novel strategy in ameliorating proliferative disease like cancers.

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Series Title: -
Call Number: T267
Publisher: Jatinangor : Fakultas Farmasi Universitas Padjadjaran., 2021
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Language: Indonesia
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Classification: T267
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