20(S)-Ginsenoside Rh2: A Promising Adjuvant Treatment for Acute Promyelocytic Leukemia
Introduction
Acute promyelocytic leukemia (APL), the M3 type of acute myeloid leukemia (AML), typically relies on all-trans retinoic acid (ATRA) as its primary treatment. While APL patients treated with ATRA exhibit a high bone marrow complete remission rate, ATRA resistance severely limits its efficacy and contributes to a poor prognosis. Recent research underscores the potential of 20(S)-ginsenoside Rh2 (GRh2) as a lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL, providing a new direction for the development of novel drugs for APL.About APL
APL, constituting 10-15% of all AML cases, is characterized by abnormal promyelocyte proliferation, with associated complications such as bone marrow dysfunction and anemia. In the 1960s and 1970s, APL is a medical emergency with high mortality rate, and API-related death is often attributed to bleeding due to coagulation disorders. With the invention and evolution of new drugs, the prognosis of APL patients has been greatly improved. The 10-year survival rate for APL patients today is estimated to be about 80-90%. Differentiation-inducing agent, such as ATRA, is an essential part for the treatment of APL. Leukemic stem cells (LSCs) and ATRA-resistant APL cells primary contributors to leukemia recurrence post-remission. Addressing these residual issues is of great importance in the pursuit of improved treatment outcomes.The association between METTL3 and ATRA-resistance in APL
METTL3 is a promising therapeutic target for ATRA resistant APL. Upregulation of METTL3, which is driven by lactylation modifications, promotes ATRA-resistance in APL, as indicated by the increased number of CD45+ leukemia cells and Giemsa positive cells in the METTL3-OE group.
The suppressive impact of GRh2 upon ATRA-resistance in APL
In vitro, GRh2 increases histone acetylation levels and considerably inhibits the lactylation level in ATRA-resistant APL cells, and promotes the apoptosis of ATRA-resistance LSCs, acting as a histone lactylation inhibitor. In addition to repressing the enzyme activity of METTL3, GRh2 dose-dependently inhibits the expression levels of METTL3 and MEETL3 and its downstream reading protein YTHDF2, YTHDF1 and YTHDC1 in ATRA-resistant APL cells. Molecular docking analysis shows that GRh2 can directly bind with METTL3.
In vivo, GRh2 suppresses METTL3 expression, tumor weight and volume, yet enhances the sensitivity to ATRA differentiation therapy in mice with ATRA-resistant APL xenograft tumors. Moreover, GRh2 treatment considerably elevates the survival of ATRA-resistant APL xenograft mice.
Conclusion
Mechanically, GRh2 can reduce ATRA resistance in APL by repressing lactylation-driven METTL3. Further exploration of this interaction could lead to the development of more effective and personalized treatment strategies for APL patients, ultimately improving their prognosis and quality of life.Reference
Cheng S, Chen L, Ying J, et al. 20(S)-ginsenoside Rh2 ameliorates ATRA resistance in APL by modulating lactylation-driven METTL3. J Ginseng Res. 2024;48(3):298-309. doi:10.1016/j.jgr.2023.12.003BONTAC Ginsenosides
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