Pterostilbene downregulates BCR/ABL and induces apoptosis of T315I-mutated BCR/ABL-positive leukemic cells

• Published in: Scientific reports Vol. 12; no. 1; p. 704
• Main Authors: Kawakami, Shohei, Tsuma-Kaneko, Mitsuyo, Sawanobori, Masakazu, Uno, Tomoko, Nakamura, Yoshihiko, Matsuzawa, Hideyuki, Suzuki, Rikio, Onizuka, Makoto, Yahata, Takashi, Naka, Kazuhito, Ando, Kiyoshi, Kawada, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.01.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Abl gene; Administration, Oral; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; BCR gene; BCR protein; Bone marrow; Caspase; Caspases - metabolism; Down-Regulation - drug effects; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Enzyme inhibitors; Extracellular signal-regulated kinase; Fusion protein; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Hematopoietic stem cells; Hematopoietic Stem Cells - pathology; Humans; Kinases; Leukemia; Leukemia - drug therapy; Leukemia - genetics; Leukemia - pathology; Mice; Mutation - genetics; NF-kappa B - metabolism; NF-κB protein; Oral administration; Progenitor cells; Proteasomes; Protein-tyrosine kinase; Proto-Oncogene Proteins c-akt - metabolism; Resveratrol; Signal transduction; Stilbenes - administration & dosage; Stilbenes - pharmacology; Tumor Cells, Cultured; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-04654-1

In this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL leukemia, in particular for those showing ABL-dependent TKI resistance.