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

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. Electronic address:

Published: March 2024

AI Article Synopsis

  • Scientists have found new cancer treatment drugs called immune checkpoint inhibitors that help improve survival rates by blocking certain proteins, but they can also have side effects because they are large.
  • This study is looking for smaller, natural medicine options to block these proteins without causing as many side effects, specifically using a plant called evening primrose.
  • The results showed that a compound from evening primrose can help battle cancer by boosting the immune system's T cells, making them better at fighting tumors and reducing their growth.

Article Abstract

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.

Purpose: 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.

Methods: 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 CD8T 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.

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Source
http://dx.doi.org/10.1016/j.phymed.2024.155370DOI Listing

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