BCI

BCI, as a selective dual-specificity phosphatase 6 (DUSP6) inhibitor, can inhibit tumor growth and macrophage inflammation.^[1].

In vitro, at low-dose of ≤2 μM and ≤4 μM, BCI showed no cytotoxic effects on RAW264.7 cells and BMMs, respectively. And at concentrations of ≤4 μM, BCI had no obvious effect on cell cycle progression or apoptosis in BMMs.^[1] In vitro experiment it shown that treatment with 1?μM BCI enhanced osteoclastogenesis by inhibiting DUSP6. Moreover, BCI increased the levels of osteoclast-related gene expression such as NFATC1, C-fos, ACP5, and DC-STAMP.^[2] In vitro efficacy test it demonstrated that treatment with 4?μm BCI obviously increased the proportion of cells expressing cleaved caspase‐3, 4?μm BCI already elicited extensive cytotoxicity in KELLY and IMR‐32 cells, and only a minority of LAN‐1 and SK‐N‐AS cells remained.^[3] In vitro, with 1 μM BCI did not affect total NCC and NCC surface expression as well as ERK1/2 phosphorylation. Treatment with 5 μM BCI can markedly increase ERK1/2 phosphorylation and decrease total NCC and NCC surface expression.^[5].

In vivo, mice were treated with 10mg/kg BCI intraperitoneally for five consecutive days per week, suppressed AKT activation and prevents tumor formation.^[4] In vivo test it exhibited that treatment with 50, 100, and 200 mg/kg BCI orally in the CPDM animal model obviously increased the number of pNrf2-positive cells in periodontal tissue and mitigated the alveolar bone loss.^[6].

References:
[1] Cai C, et al. BCI Suppresses RANKL-Mediated Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss. Front Pharmacol. 2021 Nov 1;12:772540.
[2] Zhang B, et al. DUSP6 expression is associated with osteoporosis through the regulation of osteoclast differentiation via ERK2/Smad2 signaling. Cell Death Dis. 2021 Sep 2;12(9):825.
[3] Thompson EM, et al. The cytotoxic action of BCI is not dependent on its stated DUSP1 or DUSP6 targets in neuroblastoma cells. FEBS Open Bio. 2022 Jul;12(7):1388-1405.
[4] Duan S, et al. Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis. Cell Rep. 2021 Oct 19;37(3):109870.
[5] Feng X, et al. Aldosterone modulates thiazide-sensitive sodium chloride cotransporter abundance via DUSP6-mediated ERK1/2 signaling pathway. Am J Physiol Renal Physiol. 2015 May 15;308(10):F1119-27.
[6] Zhu C, et al. The therapeutic role of baicalein in combating experimental periodontitis with diabetes via Nrf2 antioxidant signaling pathway. J Periodontal Res. 2020 Jun;55(3):381-391.

BCI 作为一种选择性双特异性磷酸酶 6 (DUSP6) 抑制剂，可以抑制肿瘤生长和巨噬细胞炎症。^[1]。

在体外，在 ≤2 μM 和 ≤4 μM 的低剂量下，BCI 分别对 RAW264.7 细胞和 BMM 没有细胞毒性作用。浓度≤4 μM时，BCI对BMM细胞周期进程或细胞凋亡无明显影响。^[1] 体外实验表明，1μM BCI通过抑制DUSP6增强破骨细胞生成。此外，BCI可提高NFATC1、C-fos、ACP5、DC-STAMP等破骨细胞相关基因的表达水平。^[2] 体外药效试验表明，4μm BCI处理明显表达裂解的 caspase-3 的细胞比例增加，4μm BCI 已经在 KELLY 和 IMR-32 细胞中引起广泛的细胞毒性，只有少数 LAN-1 和 SK-N-AS 细胞保留下来。^{[3]< /sup> 在体外，1 μM BCI 不影响总 NCC 和 NCC 表面表达以及 ERK1/2 磷酸化。用 5 μM BCI 处理可显着增加 ERK1/2 磷酸化并降低总 NCC 和 NCC 表面表达。[5]。}

在体内，小鼠每周连续 5 天腹腔注射 10mg/kg BCI，抑制 AKT 激活并防止肿瘤形成。^[4] 体内试验表明，用 50、 CPDM动物模型口服100、200 mg/kg BCI明显增加牙周组织中pNrf2阳性细胞数量，减轻牙槽骨丢失。^[6].