PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose.
PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose.
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DOI：
10.18632/oncotarget.19630
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发表时间：
2017-10-31
期刊：
影响因子：
--
通讯作者：
Spielman DM
中科院分区：
文献类型：
--
作者：
Tee SS;Park JM;Hurd RE;Brimacombe KR;Boxer MB;Massoud TF;Rutt BK;Spielman DM
癌症新陈代谢已成为干扰肿瘤生长的一个越来越有吸引力的靶点。小分子激活剂丙酮酸激酶同工酶M2(PKM2)抑制肿瘤的形成，但对已建立的肿瘤有未知的作用。我们证明，PKM2激活剂Tepp-46导致葡萄糖消耗增加，为将PKM2激活剂与有毒的葡萄糖类似物2-脱氧-D-葡萄糖(2-DG)结合提供了理论基础。联合治疗导致一系列细胞系在标准细胞培养条件下的生存能力下降，药物浓度单独使用时不起作用。这一效应在已建立的皮下肿瘤上得到了体内复制。我们进一步展示了使用超极化磁共振波谱(MRS)检测联合治疗中急性代谢差异的能力。联合治疗的肿瘤在治疗后2小时显示出更高的丙酮酸到乳酸的13C标记交换。这种非侵入性评估药物效果的能力可能会加速针对癌症新陈代谢的药物的实施和临床翻译。
Cancer metabolism has emerged as an increasingly attractive target for interfering with tumor growth. Small molecule activators of pyruvate kinase isozyme M2 (PKM2) suppress tumor formation but have an unknown effect on established tumors. We demonstrate that TEPP-46, a PKM2 activator, results in increased glucose consumption, providing the rationale for combining PKM2 activators with the toxic glucose analog, 2-deoxy-D-glucose (2-DG). Combination treatment resulted in reduced viability of a range of cell lines in standard cell culture conditions at concentrations of drugs that had no effect when used alone. This effect was replicated in vivo on established subcutaneous tumors. We further demonstrated the ability to detect acute metabolic differences in combination treatment using hyperpolarized magnetic resonance spectroscopy (MRS). Combination treated tumors displayed a higher pyruvate to lactate 13C-label exchange 2 hr post-treatment. This ability to assess the effect of drugs non-invasively may accelerate the implementation and clinical translation of drugs that target cancer metabolism.
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影响因子：
2.9
作者：
Lodi, Alessia;Woods, Sarah M.;Ronen, Sabrina M.
通讯作者：
Ronen, Sabrina M.
DOI：
10.1073/pnas.1118726109
发表时间：
2012-04-03
影响因子：
11.1
作者：
Eckel-Mahan, Kristin L.;Patel, Vishal R.;Sassone-Corsi, Paolo
通讯作者：
Sassone-Corsi, Paolo
影响因子：
8
作者：
Buzzai, M;Bauer, DE;Thompson, CB
通讯作者：
Thompson, CB
影响因子：
11.2
作者：
Bohndiek SE;Kettunen MI;Hu DE;Brindle KM
通讯作者：
Brindle KM
丙酮酸激酶M2激活剂促进四聚体形成并抑制肿瘤发生。
影响因子：
14.8
作者：
Anastasiou, Dimitrios;Yu, Yimin;Israelsen, William J.;Jiang, Jian-Kang;Boxer, Matthew B.;Hong, Bum Soo;Tempel, Wolfram;Dimov, Svetoslav;Shen, Min;Jha, Abhishek;Yang, Hua;Mattaini, Katherine R.;Metallo, Christian M.;Fiske, Brian P.;Courtney, Kevin D.;Malstrom, Scott;Khan, Tahsin M.;Kung, Charles;Skoumbourdis, Amanda P.;Veith, Henrike;Southall, Noel;Walsh, Martin J.;Brimacombe, Kyle R.;Leister, William;Lunt, Sophia Y.;Johnson, Zachary R.;Yen, Katharine E.;Kunii, Kaiko;Davidson, Shawn M.;Christofk, Heather R.;Austin, Christopher P.;Inglese, James;Harris, Marian H.;Asara, John M.;Stephanopoulos, Gregory;Salituro, Francesco G.;Jin, Shengfang;Dang, Lenny;Auld, Douglas S.;Park, Hee-Won;Cantley, Lewis C.;Thomas, Craig J.;Heiden, Matthew G. Vander
通讯作者：
Heiden, Matthew G. Vander