Melflufen, a peptide-conjugated alkylator, is an efficient anti-neo-plastic drug in breast cancer cell lines.,Cancer Medicine

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Melflufen, a peptide-conjugated alkylator, is an efficient anti-neo-plastic drug in breast cancer cell lines.
Cancer Medicine ( IF 2.9 ) Pub Date : 2020-07-27 , DOI: 10.1002/cam4.3300
Alexander Schepsky ₁ , Gunnhildur Asta Traustadottir ₁ , Jon Petur Joelsson ₁ , Saevar Ingthorsson ₁ , Jennifer Kricker ₁ , Jon Thor Bergthorsson ₂ , Arni Asbjarnarson ₁ , Thorkell Gudjonsson ₃ , Nina Nupponen ₄ , Ana Slipicevic ₄ , Fredrik Lehmann ₄ , Thorarinn Gudjonsson _{1,

2}

Affiliation

Melphalan flufenamide (hereinafter referred to as “melflufen”) is a peptide‐conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma. Due to its lipophilic nature, it readily enters cells, where it is converted to the known alkylator melphalan leading to enrichment of hydrophilic alkylator payloads. Here, we have analysed in vitro and in vivo the efficacy of melflufen on normal and cancerous breast epithelial lines. D492 is a normal‐derived nontumorigenic epithelial progenitor cell line whereas D492HER2 is a tumorigenic version of D492, overexpressing the HER2 oncogene. In addition we used triple negative breast cancer cell line MDA‐MB231. The tumorigenic D492HER2 and MDA‐MB231 cells were more sensitive than normal‐derived D492 cells when treated with melflufen. Compared to the commonly used anti‐cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo. However, melflufen was more efficient in inhibiting metastasis of MDA‐MB231 cells. Melflufen induced DNA damage was confirmed by the expression of the DNA damage proteins ƴH2Ax and 53BP1. The effect of melflufen on D492HER2 was attenuated if cells were pretreated with the aminopeptidase inhibitor bestatin, which is consistent with previous reports demonstrating the importance of aminopeptidase CD13 in facilitating melflufen cleavage. Moreover, analysis of CD13^high and CD13^low subpopulations of D492HER2 cells and knockdown of CD13 showed that melflufen efficacy is mediated at least in part by CD13. Knockdown of LAP3 and DPP7 aminopeptidases led to similar efficacy reduction, suggesting that also other aminopeptidases may facilitate melflufen conversion. In summary, we have shown that melflufen is a highly efficient anti‐neoplastic agent in breast cancer cell lines and its efficacy is facilitated by aminopeptidases.

中文翻译：

Melflufen，一种肽偶联的烷基化剂，是乳腺癌细胞系中一种有效的抗肿瘤药物。

Melphalan氟苯甲酰胺（以下称为“ melflufen”）是目前在3期临床试验中用于治疗复发性或难治性多发性骨髓瘤的肽结合药物。由于其亲脂性，它很容易进入细胞，并在那里转化为已知的烷基化剂美法仑，从而导致亲水性烷基化剂有效载荷的富集。在这里，我们已经在体外和体内分析了美氟芬对正常和癌性乳腺癌上皮细胞系的功效。D492是正常来源的非致瘤上皮祖细胞系，而D492HER2是D492的致瘤版本，过表达HER2癌基因。另外，我们使用了三阴性乳腺癌细胞系MDA-MB231。用美氟芬治疗时，致癌的D492HER2和MDA-MB231细胞比正常来源的D492细胞更敏感。与常用的抗癌药阿霉素相比，美氟芬在降低体外细胞活力方面更为有效，同时在体内具有可比的效果。但是，美氟芬在抑制MDA-MB231细胞转移方面更有效。通过DNA损伤蛋白ƴH2Ax和53BP1的表达证实了Melflufen诱导的DNA损伤。如果用氨基肽酶抑制剂Bestatin预处理细胞，则melflufen对D492HER2的作用会减弱，这与以前的报道一致，表明氨基肽酶CD13在促进melflufen裂解中的重要性。此外，CD13的分析美洛芬在抑制MDA-MB231细胞转移方面更有效。通过DNA损伤蛋白ƴH2Ax和53BP1的表达证实了Melflufen诱导的DNA损伤。如果用氨基肽酶抑制剂Bestatin预处理细胞，则melflufen对D492HER2的作用会减弱，这与以前的报道一致，表明氨基肽酶CD13在促进melflufen裂解中的重要性。另外，CD13的分析美洛芬在抑制MDA-MB231细胞转移方面更有效。通过DNA损伤蛋白ƴH2Ax和53BP1的表达证实了Melflufen诱导的DNA损伤。如果用氨基肽酶抑制剂Bestatin预处理细胞，则melflufen对D492HER2的作用会减弱，这与以前的报道一致，表明氨基肽酶CD13在促进melflufen裂解中的重要性。此外，CD13的分析D492HER2细胞的^高亚群和^低CD13亚群以及CD13的敲低表明，美氟芬功效至少部分地由CD13介导。LAP3和DPP7氨基肽酶的抑制导致相似的功效降低，表明其他氨基肽酶也可能促进美氟芬转化。总而言之，我们已经证明美洛芬是乳腺癌细胞系中的一种高效抗肿瘤药，其氨肽酶促进了其功效。

更新日期：2020-09-28

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