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1441 Alpha-Pinene As a Novel Therapeutic Agent for T-Cell Tumors

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Lymphoid Leukemias, ALL, apoptosis, Lymphomas, Non-Biological therapies, Chemotherapy, T Cell lymphoma, Diseases, Therapies, Lymphoid Malignancies, Biological Processes
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Masaya Abe, MD1*, Noboru Asada, MD, PhD2, Maiko Kimura1*, Chie Fukui3*, Daisuke Yamada4*, Ziyi Wang5*, Masayuki Miyake6*, Takeshi Takarada4*, Mitsuaki Ono5*, Michinori Aoe6*, Wataru Kitamura1*, Masayuki Matsuda1*, Takashi Moriyama1*, Akifumi Matsumura1* and Yoshinobu Maeda, MD, PhD1

1Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
2Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
3Division of Hematology, Department of Medicine, Kobe University Hospital, Kobe, Japan
4Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
5Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
6Division of Medical Support, Okayama University Hospital, Okayama, Japan

T-cell acute leukemia and lymphoma have poor prognoses, necessitating the development of novel therapeutic agents. In this study, we investigated the antitumor activity of α-pinene, a monoterpene compound, against T-cell tumors. We evaluated the effects of α-pinene on cell growth inhibition in vitro using the murine T-cell tumor cell line EL-4 and the human-derived T-cell tumor cell line Molt-4. In addition, we assessed the effects of limonene, another monoterpene with reported tumor-suppressive effects, as a comparative agent.

Both α-pinene and limonene demonstrated concentration- and time-dependent inhibition of cell growth in both the EL-4 and Molt-4 cell lines (Figure 1). Moreover, α-pinene exhibited greater potency than limonene in inhibiting the growth of various hematologic malignancies. Importantly, α-pinene and limonene had minimal effects on the growth of normal murine spleen T cells. Further investigation of the mechanisms of action of α-pinene revealed its ability to induce apoptosis and cell cycle arrest in EL-4 and Molt-4 cells. Transcriptomic profiling of α-pinene-treated EL-4 cells using RNA-seq identified differentially expressed genes associated with cellular damage and mitochondrial dysfunction. Increased intracellular ROS levels and mitochondrial impairment were observed in the T-cell tumors treated with α-pinene. The activation of intrinsic apoptotic pathways involving EGR1, p53, BCL-2, and BAX was found to contribute to α-pinene-induced apoptosis in T-cell tumors. Moreover, α-pinene inhibited the NF-κB signaling pathway, resulting in the reduced nuclear translocation of NF-κB p65 and decreased total intracellular NF-κB p65 levels in EL-4 cells. Additionally, we discovered that α-pinene induced ferroptosis, a newly identified programmed cell death process, in EL-4 cells through lipid peroxidation and iron accumulation. Activation of the system xc/GSH/GPX4 axis and upregulation of iron transporters, such as Slc39a8 and TfR1, were observed in α-pinene-induced ferroptosis. Treatment with the ferroptosis inhibitor Fer-1 partially reversed the tumor-inhibiting effect of α-pinene in EL-4 cells. Finally, we administrated α-pinene to mice subcutaneously injected with luciferase-expressing EL-4 to evaluate the efficacy of α-pinene in vivo. The tumor growth was significantly inhibited by α-pinene treatment (vehicle: 1055 ± 101 mm3; α-pinene: 701 ± 82 mm3, p < 0.01, Figure 2) without adverse effects on body weight or behavior. Immunohistochemistry analyses revealed a significant increase of CD8+ T-cells (vehicle: 8.1 ± 2.7 cells / field of view; α-pinene: 43.1 ± 12.2 cells / field of view , p < 0.05) and NK1.1+ cells (vehicle: 5.1 ± 1.0 cells / field of view ; α-pinene: 41.1 ± 9.8 cells / field of view , p < 0.01) in the tumors, suggesting that α-pinene may have an indirect antitumor effect by recruiting immune cells into tumors.

Overall, our findings demonstrate the antitumor activity of α-pinene against T-cell tumors through the induction of apoptosis, cell cycle arrest, and ferroptosis. α-Pinene shows promise as a potential therapeutic agent for T-cell tumors and warrants further investigation for its clinical application.

Disclosures: Asada: Astellas: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Abbvie: Speakers Bureau; Asahi KASEI Co., Ltd.: Speakers Bureau; Meiji Seika Phama Co. Ltd.: Speakers Bureau; Nippon Shinyaku Co., Ltd: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Maeda: Eisai Pharmaceutical Co., Ltd.: Honoraria; AstraZeneca: Research Funding; Astellas: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Novartis Pharma: Research Funding, Speakers Bureau; Nippon Shinyaku Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria.

*signifies non-member of ASH