Smac-mimetic enhances antitumor effect of standard chemotherapy in ovarian cancer models via Caspase 8-independent mechanism.
Smac-mimetic enhances antitumor effect of standard chemotherapy in ovarian cancer models via Caspase 8-independent mechanism.
复制标题
DOI：
10.1038/s41420-021-00511-2
复制
发表时间：
2021-06-04
影响因子：
7
通讯作者：
Annunziata CM
中科院分区：
文献类型：
--
作者：
Hernandez LF;Dull AB;Korrapati S;Annunziata CM
卵巢癌是美国最致命的妇科癌症。标准治疗包括手术，然后是依赖于肿瘤细胞凋亡的化疗。大多数患有晚期疾病的妇女会复发，这表明这种疾病的特征是对化疗的原发性和获得性耐药性，并且非常需要新的治疗方法。卵巢癌中Caspase 8的低表达水平与对凋亡化疗的抵抗相关，并且具有低Caspase 8水平的患者亚群在标准治疗后表现出较差的总生存期。我们假设，当暴露于标准化疗时，低半胱天冬酶8功能降低了癌细胞进行凋亡的能力，并且第二种来源于caspase激活剂（Smac）-模拟物与化疗联合可能增加细胞死亡。在这里，我们表明，与Smac模拟物的组合治疗可以靶向具有低Caspase 8的肿瘤细胞并诱导坏死性细胞死亡。我们研究了将Smac模拟物加入卡铂和紫杉醇治疗表达野生型和低Caspase 8水平的卵巢癌细胞的体外作用，这导致细胞死亡增加2-4倍。携带皮下或腹膜内卵巢异种移植物的小鼠显示出与野生型肿瘤相比更大的半胱天冬酶8缺陷型肿瘤的侵袭性;与化疗和Smac模拟物组合的体内治疗导致低半胱天冬酶8异种移植物生长减少>50%，以及显著提高的总存活率，特别是当与紫杉醇同时给予时。令人惊讶的是，与在连续的治疗日给予Smac模拟物相比，在与卡铂相同的一天给予Smac模拟物降低了小鼠存活率。拮抗作用与DNA损伤标记物的减少有关，强调了优化给药时机的重要性。需要对这些方法进行临床验证，以提高目前标准卵巢癌治疗的有效性。
Ovarian cancer is the most lethal gynecological cancer in the US. Standard treatment consists of surgery followed by chemotherapies relying on apoptotic tumor cell death. Most women with advanced stage disease will relapse, suggesting that this disease is characterized by primary and acquired resistance to chemotherapy, and novel approaches to treatment are greatly needed. Low Caspase 8 expression levels in ovarian cancers correlate with resistance to apoptotic chemotherapy, and a subpopulation of patients with low Caspase 8 levels exhibit poorer overall survival after standard-of-care treatment. We hypothesized that low Caspase 8 function reduces the ability of cancer cells to undergo apoptosis when exposed to standard chemotherapy and that second mitochondria-derived activator of caspases (Smac)-mimetics could increase cell death in combination with chemotherapy. Here we show that combination treatment with a Smac-mimetic can target tumor cells with low Caspase 8 and induce necroptotic cell death. We investigated the in vitro effect of Smac-mimetic added to carboplatin and paclitaxel treatment of ovarian cancer cells expressing wild type and low Caspase 8 levels, which resulted in a 2–4-fold enhancement of cell death. Mice bearing subcutaneous or intraperitoneal ovarian xenografts showed greater aggressiveness of Caspase 8-deficient versus wild-type tumors; combined in vivo treatment with chemotherapy and Smac-mimetic resulted in >50% decrease in low Caspase 8 xenograft growth, as well as significantly enhanced overall survival, especially when given simultaneously with paclitaxel. Surprisingly, Smac-mimetic on the same day as carboplatin decreased mouse survival compared to when it was given on a sequential day of treatment. The antagonism was associated with a decrease in DNA damage markers, emphasizing the importance of optimizing timing of drug administration. Clinical validation of such approaches is needed to increase the effectiveness of current standard ovarian cancer treatment.
登录
查看更多内容
影响因子：
5.7
作者：
Benetatos, Christopher A.;Mitsuuchi, Yasuhiro;Chunduru, Srinivas K.
通讯作者：
Chunduru, Srinivas K.
影响因子：
64.8
作者：
Bell, D.;Berchuck, A.;Birrer, M.;Chien, J.;Cramer, D. W.;Dao, F.;Dhir, R.;DiSaia, P.;Gabra, H.;Glenn, P.;Godwin, A. K.;Gross, J.;Hartmann, L.;Huang, M.;Huntsman, D. G.;Iacocca, M.;Imielinski, M.;Kalloger, S.;Karlan, B. Y.;Levine, D. A.;Mills, G. B.;Morrison, C.;Mutch, D.;Olvera, N.;Orsulic, S.;Park, K.;Petrelli, N.;Rabeno, B.;Rader, J. S.;Sikic, B. I.;Smith-McCune, K.;Sood, A. K.;Bowtell, D.;Penny, R.;Testa, J. R.;Chang, K.;Dinh, H. H.;Drummond, J. A.;Fowler, G.;Gunaratne, P.;Hawes, A. C.;Kovar, C. L.;Lewis, L. R.;Morgan, M. B.;Newsham, I. F.;Santibanez, J.;Reid, J. G.;Trevino, L. R.;Wu, Y. -Q.;Wang, M.;Muzny, D. M.;Wheeler, D. A.;Gibbs, R. A.;Getz, G.;Lawrence, M. S.;Cibulskis, K.;Sivachenko, A. Y.;Sougnez, C.;Voet, D.;Wilkinson, J.;Bloom, T.;Ardlie, K.;Fennell, T.;Baldwin, J.;Gabriel, S.;Lander, E. S.;Ding, L.;Fulton, R. S.;Koboldt, D. C.;McLellan, M. D.;Wylie, T.;Walker, J.;O'Laughlin, M.;Dooling, D. J.;Fulton, L.;Abbott, R.;Dees, N. D.;Zhang, Q.;Kandoth, C.;Wendl, M.;Schierding, W.;Shen, D.;Harris, C. C.;Schmidt, H.;Kalicki, J.;Delehaunty, K. D.;Fronick, C. C.;Demeter, R.;Cook, L.;Wallis, J. W.;Lin, L.;Magrini, V. J.;Hodges, J. S.;Eldred, J. M.;Smith, S. M.;Pohl, C. S.;Vandin, F.;Raphael, B. J.;Weinstock, G. M.;Mardis, R.;Wilson, R. K.;Meyerson, M.;Winckler, W.;Getz, G.;Verhaak, R. G. W.;Carter, S. L.;Mermel, C. H.;Saksena, G.;Nguyen, H.;Onofrio, R. C.;Lawrence, M. S.;Hubbard, D.;Gupta, S.;Crenshaw, A.;Ramos, A. H.;Ardlie, K.;Chin, L.;Protopopov, A.;Zhang, Juinhua;Kim, T. M.;Perna, I.;Xiao, Y.;Zhang, H.;Ren, G.;Sathiamoorthy, N.;Park, R. W.;Lee, E.;Park, P. J.;Kucherlapati, R.;Absher, D. M.;Waite, L.;Sherlock, G.;Brooks, J. D.;Li, J. Z.;Xu, J.;Myers, R. M.;Laird, P. W.;Cope, L.;Herman, J. G.;Shen, H.;Weisenberger, D. J.;Noushmehr, H.;Pan, F.;Triche, T., Jr.;Berman, B. P.;Van den Berg, D. J.;Buckley, J.;Baylin, S. B.;Spellman, P. T.;Purdom, E.;Neuvial, P.;Bengtsson, H.;Jakkula, L. R.;Durinck, S.;Han, J.;Dorton, S.;Marr, H.;Choi, Y. G.;Wang, V.;Wang, N. J.;Ngai, J.;Conboy, J. G.;Parvin, B.;Feiler, H. S.;Speed, T. P.;Gray, J. W.;Levine, D. A.;Socci, N. D.;Liang, Y.;Taylor, B. S.;Schultz, N.;Borsu, L.;Lash, A. E.;Brennan, C.;Viale, A.;Sander, C.;Ladanyi, M.;Hoadley, K. A.;Meng, S.;Du, Y.;Shi, Y.;Li, L.;Turman, Y. J.;Zang, D.;Helms, E. B.;Balu, S.;Zhou, X.;Wu, J.;Topal, M. D.;Hayes, D. N.;Perou, C. M.;Getz, G.;Voet, D.;Saksena, G.;Zhang, Junihua;Zhang, H.;Wu, C. J.;Shukla, S.;Cibulskis, K.;Lawrence, M. S.;Sivachenko, A.;Jing, R.;Park, R. W.;Liu, Y.;Park, P. J.;Noble, M.;Chin, L.;Carter, H.;Kim, D.;Karchin, R.;Spellman, P. T.;Purdom, E.;Neuvial, P.;Bengtsson, H.;Durinck, S.;Han, J.;Korkola, J. E.;Heiser, L. M.;Cho, R. J.;Hu, Z.;Parvin, B.;Speed, T. P.;Gray, J. W.;Schultz, N.;Cerami, E.;Taylor, B. S.;Olshen, A.;Reva, B.;Antipin, Y.;Shen, R.;Mankoo, P.;Sheridan, R.;Ciriello, G.;Chang, W. K.;Bernanke, J. A.;Borsu, L.;Levine, D. A.;Ladanyi, M.;Sander, C.;Haussler, D.;Benz, C. C.;Stuart, J. M.;Benz, S. C.;Sanborn, J. Z.;Vaske, C. J.;Zhu, J.;Szeto, C.;Scott, G. K.;Yau, C.;Hoadley, K. A.;Du, Y.;Balu, S.;Hayes, D. N.;Perou, C. M.;Wilkerson, M. D.;Zhang, N.;Akbani, R.;Baggerly, K. A.;Yung, W. K.;Mills, G. B.;Weinstein, J. N.;Penny, R.;Shelton, T.;Grimm, D.;Hatfield, M.;Morris, S.;Yena, P.;Rhodes, P.;Sherman, M.;Paulauskis, J.;Millis, S.;Kahn, A.;Greene, J. M.;Sfeir, R.;Jensen, M. A.;Chen, J.;Whitmore, J.;Alonso, S.;Jordan, J.;Chu, A.;Zhang, Jinghui;Barker, A.;Compton, C.;Eley, G.;Ferguson, M.;Fielding, P.;Gerhard, D. S.;Myles, R.;Schaefer, C.;Shaw, K. R. Mills;Vaught, J.;Vockley, J. B.;Good, P. J.;Guyer, M. S.;Ozenberger, B.;Peterson, J.;Thomson, E.
通讯作者：
Thomson, E.
影响因子：
4.7
作者：
Hernandez L;Kim MK;Lyle LT;Bunch KP;House CD;Ning F;Noonan AM;Annunziata CM
通讯作者：
Annunziata CM
影响因子：
11.2
作者：
Hernandez L;Hsu SC;Davidson B;Birrer MJ;Kohn EC;Annunziata CM
通讯作者：
Annunziata CM
影响因子：
254.7
作者：
Siegel, Rebecca L.;Miller, Kimberly D.;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin