Abstract
Differentiation therapy has been successfully applied clinically in cases of acute promyelocytic leukemia (APL), but few differentiation-induction agents other than all-trans retinoic acid (ATRA) have been discovered clinically. Based on our previously reported neuritogenic differentiation activity of synthetic dimeric derivatives of securinine, we explored the leukemia differentiation-induction activity of such as compound, SN3-L6. It was found that SN3-L6 induces transdifferentiation of both acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) cells but unexpectedly, a new transdifferentiation pathway from APL cells to morphologically and immunologically normal megakaryocytes and platelets were discovered. SN3-L6 fails to induce transdifferentiation of ATRA–produced mature granulocytes into megakaryocytes, indicating its selectivity between mature and immature cells. SN3-L6 induces CML K562 cells to transdifferentiate into apoptotic megakaryocytes but without platelet formation, indicating a desirable selectivity between different leukemia cells. Our data illuminate a differentiation gap between AML cells and platelets, and promises applications in leukemia differentiation therapy strategy.
Highlights
IntroductionThe most common method for treatment of leukemia involves chemotherapeutic agents that kill cancer cells but have a number of severely toxic sideeffects
Leukemia is characterized by a blockage of cell differentiation (Fig. 1)
HL60 cells were selected for our study and an interesting phenomenon was observed, that cells treated with SN3-L6 grew larger and brighter 2 d later than did cells treated only with dimethyl sulfoxide (DMSO)
Summary
The most common method for treatment of leukemia involves chemotherapeutic agents that kill cancer cells but have a number of severely toxic sideeffects. An alternative treatment of leukemia, especially acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (AML), involves medicines that alter tumor growth by inducing terminal differentiation. Agents that act as terminal differentiation inducers include all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3), that can cure APL1–5. Since ATRA was successfully applied clinically[7], differentiation therapy became an effective treatment for APL in 2009, but few Securinine is an alkaloid found in the leaves of Securinega, Phyllanthus, and Flueggea genera[11]. Our previous research revealed the effective neuritogenic differentiation activity of some synthetic dimeric securinine derivatives[12,13]. We have explored the leukemia differentiation induction activity of synthetic securinine derivatives and found that a synthetic securinine
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