Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of cMYC expression and induction of cyclin G2 expression in human leukemia HL60 cells (Maniwa Y, et al.)
Acute myeloid leukemia (AML) is the most common type of leukemia in adults and remains one of the most difficult hematological malignancies to treat. Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, alternative or combination therapies are needed to improve the prognosis and survival of patients, and the results of a Japanese study published in the International Journal of Oncology point to a combination including Vitamin K2 could be the answer.
Japanese researchers demonstrate that the combined treatment of Vitamin K2 and Cotylenin A (CAN) synergistically induced monocytic differentiation in HL60 cells. This combined treatment also synergistically induced NBT-reducing activity and non-specific esterasepositive cells, as well as morphological changes to monocyte/macrophage-like cells. Vitamin K2 and CNA cooperatively inhibited the proliferation of HL60 cells in short- and long-term cultures. This treatment also induced growth arrest at the G1 phase. Further, although 5 μg/ml CNA or 5 μM vitamin K2 alone reduced cMYC gene expression in HL60 cells to approximately 45% or 80% that of control cells, respectively, the combined treatment almost completely suppressed cMYC gene expression.
“We also demonstrated that the combined treatment of vitamin K2 and cotylenin A synergistically induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest,” the researchers write. “These results suggest that the combination of vitamin K2 and cotylenin A has therapeutic value in the treatment of acute myeloid leukemia.”
Katarzyna Maresz, PhD, president of the International Science and Health Foundation, explains that the researchers likely used synthetic Vitamin K2 analog (as menaquinone-4, MK-4) in this study. Vitamin K2 as MK-4 has been approved as an anti-osteoporotic drug in Japan, and the safety of the long-term administration of Vitamin K2 has been well established.
“As Vitamin K2 is a naturally occurring, safe, and clinically utilized agent, the authors searched for the substances capable of inducing cell differentiation and the expression of cyclin G2, and that can also strongly suppress the expression of cMYC in leukemia cells,” says Dr. Maresz. “They found that the treatment with Vitamin K2 plus CNA induced functional and morphological differentiation as well as growth arrest in AML cell line. Furthermore, this treatment almost completely suppressed the expression of cMYC and markedly induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest. Therefore, their results suggest that Vitamin K2 and CAN is more than an attractive combination for effective differentiation therapy in human myeloid leukemia, but it has a true therapeutic value.”
Reference: Maniwa Y, Kasukabe T, Kamakura S. Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of cMYC expression and induction of cyclin G2 expression in human leukemia HL60 cells. Int J Oncol. 2015 Jun 4. doi: 10.3892/ijo.2015.3028. [Epub ahead of print]