ZYH005, a novel DNA intercalator, overcomes all-trans retinoic acid resistance in acute promyelocytic leukemia

Abstract

Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)–one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.

2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia

“…In addition, we evaluated the effect of 2BP on ATO in APL murine model. 31 Consistent with the in vitro data ( Online Supplementary Figure S4A ), administration of ATO/2BP extended the survival of leukemic mice compared to that in the ATO-treated group ( Online Supplementary Figure S4B ). These data supported that 2BP enhanced the effect of ATO on APL in vivo .…”

“…ATO is also used as the best salvage therapy agent for ATRA-resistant APL patients. 15,19,20,31 Mechanistically, ATO induced PML-RARα degradation through direct binding to cysteine residues in PML moiety of the fusion protein. 51 However, resistance to ATO in APL was reported by several groups.…”

20(S)-ginsenoside Rh2 induces caspase-dependent promyelocytic leukemia-retinoic acid receptor A degradation in NB4 cells via Akt/Bax/caspase9 and TNF-α/caspase8 signaling cascades

“…PML-RARA degradation mainly depends on proteasomes [ 3 , 6 ], autophagy [ 7 ], and caspase [ 8 , 9 ]. From the three mechanisms of PML-RARA degradation described above, as well as caspase, a key target of GRh2, we suspected that GRh2-induced fusion protein degradation was dependent on caspase cleavage activation.…”

“…Both can promote degradation of the PML-RARA fusion protein [ 2 , 5 ]. PML-RARA is degraded via three mechanisms: proteasome degradation, which is also the main mechanism in ATO-induced fusion protein degradation [ 3 , 6 ], autophagy-dependent degradation [ 7 ], and caspase-dependent degradation [ 8 , 9 ]. The latter two are partially involved in ATRA-induced fusion protein degradation [ 10 ].…”

The Inhibition of RNA Viruses by Amaryllidaceae Alkaloids: Opportunities for the Development of Broad‐Spectrum Anti‐Coronavirus Drugs

“…They reported that the antiviral activity they observed was triggered by low‐level DNA damage which, in turn, activated the IFN‐I signalling pathway and thereby invoked host immune responses. In 2018, Tong and co‐workers described the synthesis of a highly selective DNA‐intercalator based on the narciclasine framework called ZYH005 (compound 18 , Figure 6) with a dsDNA binding constant of 4.1×10 4 M −1 [148] . We have previously developed a synthetic route to the natural product crinasiadine, which embodies the phenanthridinone core of ZYH005.…”