The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation

Abstract

Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.

Research Progress in the Pharmacological Activities, Toxicities, and Pharmacokinetics of Sophoridine and Its Derivatives

“…Recently, Zhao et al (2020) found that compound 5 ( Figure 5 ) induced DNA breakage and cell apoptosis by blocking STAT5a nuclear translocation and inhibiting STAT5a phosphorylation at 694 and 780. 38 Compared to other derivatives, compound 5 also displayed outstanding water solubility and lower toxicity properties, and its synthesis is straightforward, suggesting that it could be applied as an anti-cancer compound and, therefore, should be explored further.…”

“…37 Recently, Zhao et al (2020) found that compound 5 (Figure 5) induced DNA breakage and cell apoptosis by blocking STAT5a nuclear translocation and inhibiting STAT5a phosphorylation at 694 and 780. 38 Compared to other derivatives, compound 5 also displayed outstanding water solubility and lower toxicity properties, and its synthesis is straightforward, suggesting that it could be applied as an The synthesis of novel sophoridine derivatives using acyclic aryloxy phosphoramidate mustard can greatly improve sophoridine's anti-cancer activity. For instance, compound 6a-6e, containing a phosphoramidate mustard motif substituted at the lactam ring-opened sophoridine skeleton was shown to markedly suppress the viability of S180 and H22 cells (IC 50 = 1.01-3.56 μM).…”

SALIS transcriptionally represses IGFBP3/Caspase-7-mediated apoptosis by associating with STAT5A to promote hepatocellular carcinoma

“…STAT5A has been previously designed as a strategic target in the antitumor treatment with IMB-HDC, in which IMB-HDC plays a proapoptotic role by reducing STAT5A phosphorylation and nuclear translocation [ 45 ]. The suppression of STAT5A signaling pathway also promoted apoptosis in osteosarcoma [ 46 ].…”

Tumor microenvironment: a prospective target of natural alkaloids for cancer treatment

“…Lappaconitine inhibits the production of NO, PGE2 and TNF- α by inhibiting NF-kB and MAPK signaling pathways. Paclitaxel skews TAMs towards an immunocompetent profile via TLR4, which might contribute to the antitumor effect of PCX [ 53 , 70 – 73 , 76 – 82 , 84 , 85 , 88 , 90 ] MSCs/CSCs VEGF, TRAIL Ptx-PLGA NP-primed MSCs had enhanced sustained Ptx release in the form of free Ptx and Ptx NPs. Ptx transfer from MSCs to glioma cells could induce tumor cell death.…”

“…What's more, Sophoridine directly inhibits the cell viability of HepG2 by regulating PTEN/PI3K/AKT, Caspase-3/9 and Matrix metalloproteinase (MMP)-2/9 signal pathways. In addition, Sophoridine also inhibits the migration of macrophages by reducing the expression of CCR2[80][81][82]. Sophoridine evidently activates Hippo and p53 signal pathways to inhibit the occurrence and development of lung cancer[78].…”