Venetoclax

Venetoclax (VTC) is an oral selective BCL-2 inhibitor. The main mechanism of action of VTC is the activation of BAK and BAX, which results in mitochondrial outer membrane permeabilization (MOMP), which leads to cell apoptosis. The cellular growth is inhibited, which results in apoptosis of tumor cell lines and delayed tumour progression with improved overall survival. VTC is a highly selective BCL-2 specific with low toxicity and shows cytotoxicity in several hematologic malignancies including MM. The non-essential role of BCL-2 in many normal cells and overexpression of BCL-2 in blood malignancies including MM provide it with the benefit over the conventional cytotoxic drugs.

Fig. 1 Mechanisms of cancer suppression by venetoclax. (Cao Q, et al. 2023)

Venetoclax (Vene) is one of the most commonly used chemotherapeutic drugs in AML treatment. But its specificity to leukemia cells is limited, and more importantly, serious side effects and drug resistance problems are also likely to occur. Zhang L et al used l-phenylalanine as a good nanocarrier for Vene to develop Vene@8P6 for targeted drug delivery to treat AML. Vene@8P6 was then employed to AML mouse models and human AML cell lines. In vitro, THP-1 and HL60 cells take up Vene@8P6 nanoparticles fast. The taken-up Vene@8P6 induced serious DNA damage, high level of ROS production, high apoptosis rate, and low cell proliferation, compared to free Vene treatment. In vivo, Vene@8P6 exhibited more efficient accumulation in leukemia cells rather than normal hematopoietic cells in bone marrow and major organs of AML mice, determined by both bioluminescence imaging and flow cytometry analysis. Vene@8P6 treatment significantly alleviated drug side effects and improved AML therapeutic efficacy.

Fig. 2 L-phenylalanine nanocarriers deliver venetotok in acute myeloid leukemia. (Zhang L, et al. 2025)