Positive Health Online

Abstract

LEE and COLLEAGUES,  (1)Korean Medicine Application Center, Korea Institute of Oriental Medicine  (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; (2)National Development Institute of Korea Medicine, 27, Wondogwandeok-gil,  Jangheung-eup, Jangheung-gun, Jeollanam-do 59319, Republic of Korea; (3)New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80, Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea; (4)National Development Institute of Korea Medicine, 94, Hwarang-ro, Gyeongsan-si, Gyeongsangbuk-do 38540, Republic of Korea; (5)Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea. : jang-gichoi@kiom.re.kr.; (6)Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea; Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), 70, Cheomdan-ro, Dong-gu, Daegu 41062, Republic of Korea.: hschung@kiom.re.kr.  studied the antitumour potential of evening primrose (Oenothera biennis) root extract, using a novel class of immunotherapy drugs.

Background

The emergence of immune checkpoint inhibitors, a novel class of immunotherapy drugs, represents a major breakthrough in cancer immunotherapy, substantially improving patient survival post-treatment. Blocking programmed death-ligand 1 (PD-L1) and programmed death protein-1 (PD-1) has demonstrated promising clinical results in various human cancer types. The US FDA has recently permitted only monoclonal antibody (mAb)-based PD-L1 or PD-1 blockers. Although these antibodies exhibit high antitumor efficacy, their size- and affinity-induced side effects limit their applicability. Goal: As small-molecule-based PD-1/PD-L1 blockers capable of reducing the side effects of antibody therapies are needed, this study focuses on exploring natural ingredient-based small molecules that can target hPD-L1/PD-1 using herbal medicines and their components.

Methodology

The antitumor potential of evening primrose (Oenothera biennis) root extract (EPRE), a globally utilized traditional herbal medicine, folk remedy, and functional food, was explored. A coculture system was established using human PD-L1-expressed murine MC38 cells (hPD-L1-MC38s) and CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) expressing humanized PD-1. The in vivo experiments utilized a colorectal cancer (CRC) C57BL/6 J mouse model bearing MC38 cells expressing humanized PD-L1 and PD-1 proteins.

Results

EPRE and its active compound oenothein B effectively hindered the molecular interaction between hPD-L1 and hPD-1. EPRE stimulated tumor-specific T lymphocytes of a hPD-L1/PD-1 CRC mice. This action resulted in the elevated infiltration of cytotoxic CD8+T lymphocytes and subsequent tumor growth reduction. Moreover, the combined therapy of oenothein B, a PD-1/PD-L1 blocker, and FOLFOX (5-fluorouracil plus oxaliplatin) cooperatively suppressed hPD-L1-MC38s growth in the ex vivo model through activated CD8+ TIL antitumor immune response. Oenothein B exhibited a high binding affinity for hPD-L1 and hPD-1. We believe that this study is the first to uncover the inhibitory effects of EPRE and its component, oenothein B, on PD-1/PD-L1 interactions.

Conclusion

This study identified a promising small-molecule candidate from natural products that blocks the hPD-L1/PD-1 signaling pathway. These findings emphasize the potential of EPRE and oenothein B as effective anticancer drugs. Copyright © 2024. Published by Elsevier GmbH.  Conflict of interest statement: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

Lee EJ(1), Kim YS(1), Kim JH(1), Woo KW(2), Park YH(3), Ha JH(3), Li W(1), Kim TI(1), An BK(4), Cho HW(2), Han JH(1), Choi JG(5), Chung HS(6). Uncovering the colorectal cancer immunotherapeutic potential: Evening primrose (Oenothera biennis) root extract and its active compound oenothein B targeting the PD-1/PD-L1 blockade. Phytomedicine. ;125:155370. doi: 10.1016/j.phymed.2024.155370. Epub Jan 17 2024.  Mar 2024.