PD 0332991, as an orally active potent and highly selective inhibitor of CDK4 and CDK6 kinases, can block pRb phosphorylation and subsequently inducing G1 arrest in sensitive cell lines in low nanomolar concentrations. [1][2]
In vitro, single treatment with 8 μmol/L or 16 μmol/L gefinitib inhibited PC-9 cell proliferation.[3] In vitro efficacy test it shown that PD-0332991 acted as a concentration-dependent inhibitor of cell proliferation with an IC50 of 0.65 and 0.58 μM, respectively, in HEC1A and HEC108 cells, however, PD-0332991 did not inhibit cell proliferation in ECC and TEN cells, even at concentrations of up to 1 μM.[4] PD-0332991 has G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation in RCC cell lines with IC50 values ranged from 25.0 nM to 700 nM. [5] PD 0332991 inhibited the AN, RY, G401 and NS cell lines with IC50 of 0.01 μM, 0.01 μM, 0.06 μM, and 0.6 μM, respectively. And PD 0332991 at 0 to 1.0 μM concentrations induced G1 arrest in the AN, RY, G401 and NS cell lines in a concentration-dependent manner, but had no effect on YM cells.[6]
In vivo, treatment with 150 mg/kg PD 0332991 and 100 mg/kg gefitinib inhibited tumor growth, all of the mice had a tumor volume < 30 mm3 after 14 days of treatment, and 20% (2/10) of the mice were completely cured without relapse.[3] In vivo, nu/nu BALB/c nude mice with EC109 cells s.c. were treated with 150 mg/kg orally PD‐0332991, the results shown that PD‐0332991 significantly inhibited the growth curve (tumour volume versus time curve) of EC109 tumours. And the tumour weight in the PD‐0332991‐treated mice was obviously lower than the vehicle‐treated mice.[7]
参考文献:
[1]Fry DW, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.?Mol Cancer Ther.?2004;3:1427–1438.
[2]Saab R, et al. Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells.?Mol Cancer Ther.?2006;5:1299–1308. doi:?10.1158/1535-7163.MCT-05-0383.?
[3]Liu M, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, sensitizes lung cancer cells to treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Oncotarget. 2016 Dec 20;7(51):84951-84964.?
[4]Tanaka T, et al. The efficacy of the cyclin-dependent kinase 4/6 inhibitor in endometrial cancer. PLoS One. 2017 May 4;12(5):e0177019.?
[5]Logan JE, et al. PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res. 2013 Aug;33(8):2997-3004.
[6]Katsumi Y, et al. Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression. Biochem Biophys Res Commun. 2011 Sep 16;413(1):62-8.?
[7] Chen L, et al. Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells. Br J Pharmacol. 2017 Aug;174(15):2427-2443.
PD 0332991 作为 CDK4 和 CDK6 激酶的口服活性强效和高选择性抑制剂，可以在低纳摩尔浓度下阻断 pRb 磷酸化并随后在敏感细胞系中诱导 G1 期停滞。 [1][2]
在体外，8 μmol/L或16 μmol/L吉非替尼单药处理可抑制PC-9细胞增殖。[3] 体外药效试验表明，PD-0332991作为浓度细胞增殖依赖性抑制剂，在 HEC1A 和 HEC108 细胞中的 IC50 分别为 0.65 和 0.58 μM，然而，PD-0332991 不抑制 ECC 和 TEN 细胞中的细胞增殖，即使在一定浓度下高达 1 μM。[4] PD-0332991 在 RCC 细胞系中具有 G0/G1 细胞周期停滞、诱导晚期细胞凋亡和阻断 RB 磷酸化，IC 为 50 值范围从 25.0 nM 到 700 nM。 [5] PD 0332991 抑制 AN、RY、G401 和 NS 细胞系，IC50 分别为 0.01 μM、0.01 μM、0.06 μM 和 0.6 μM。 0 至 1.0 μM 浓度的 PD 0332991 以浓度依赖性方式诱导 AN、RY、G401 和 NS 细胞系的 G1 期阻滞，但对 YM 细胞没有影响。[6]/ p>\n 在体内，用 150 mg/kg PD 0332991 和 100 mg/kg 吉非替尼治疗可抑制肿瘤生长，所有小鼠的肿瘤体积均为 <；治疗14天后30 mm3，20%（2/10）的小鼠完全治愈，无复发。[3]体内，nu/nu BALB/c裸鼠皮下EC109细胞口服 150 mg/kg PD-0332991，结果显示 PD-0332991 显着抑制 EC109 肿瘤的生长曲线（肿瘤体积与时间曲线）。并且 PD-0332991 处理的小鼠的肿瘤重量明显低于载体处理的小鼠。[7] Cell lines Human ESCC cell lines EC109 and EC9706 cells Preparation Method Cellular senescence was assayed by measuring senescence‐associated β‐galactosidase (SA‐β‐gal) activity. Cells were grown in 6‐well flat‐bottom plates for 24 h and then treated without or with 2.5 μM PD‐0332991 for 6 days. Reaction Conditions 2.5 μM; for 6 days Applications Treatment with PD‐0332991 drastically increased the activity of SA‐β‐gal, a marker for senescent cells in EC109 and EC9706 cells. Animal models Female 6-week-old athymic nude mice (BALB/c Slc-nu/nu) Preparation Method In mice bearing human endometrial cancer, daily p.o. dosing for 21 days with PD-0332991 (50 or 150 ng/kg) suppressed tumor growth. Dosage form 50 or 150 ng/kg; p.o. Applications The Ki67 index in the PD-0332991-treated group was significantly lower than that in the control group. Furthermore, the phospho-Rb expression of the PD-0332991-treated group was significantly lower than that in the control group. 参考文献: [1]. Chen L, et al. Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells. Br J Pharmacol. 2017 Aug;174(15):2427-2443.? [2]. Tanaka T, et al. The efficacy of the cyclin-dependent kinase 4/6 inhibitor in endometrial cancer. PLoS One. 2017 May 4;12(5):e0177019.?Protocol
Cell experiment [1]:
Animal experiment [2]:
动态评分
0.0