Combined inhibition of Ref-1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co-culture models.
Combined inhibition of Ref-1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co-culture models.
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DOI：
10.1111/jcmm.16132
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Fishel ML
中科院分区：
文献类型：
--
作者：
Caston RA;Shah F;Starcher CL;Wireman R;Babb O;Grimard M;McGeown J;Armstrong L;Tong Y;Pili R;Rupert J;Zimmers TA;Elmi AN;Pollok KE;Motea EA;Kelley MR;Fishel ML
随着大量分子靶向药物在癌症中的研究，显然需要了解哪些途径可以与多个药物同时靶向，从而对肿瘤产生最大的杀伤作用。联合疗法在胰腺等难以治疗的癌症中提供了最大的希望。REF-1是一种多功能蛋白，参与氧化还原信号转导，激活转录因子，如核因子-κB、AP-1、α和STAT3。以前，我们已经证明了Ref-1(氧化还原因子-1)和STAT3的双重靶向是协同的，并降低了胰腺癌细胞的细胞存活率。这里提供的数据对这项工作进行了广泛的扩展，并为多种癌症类型中STAT3和Ref-1的关系提供了进一步的见解。使用靶向小分子抑制剂，Ref-1氧化还原信号与STAT3激活一起被阻断，并在存在和不存在相关肿瘤微环境的情况下评估肿瘤生长。我们的研究利用定量聚合酶链式反应、细胞毒性和体内肿瘤和肿瘤相关成纤维细胞(CAF)反应的分析来确定Ref-1和STAT3抑制剂的协同作用。总体而言，在体内，在CAF存在的情况下生长的胰腺肿瘤对STAT3和Ref-1抑制的组合敏感。在体外，膀胱癌和胰腺癌的协同反应最强。通过使这两条重要的通路失效，这种联合疗法有能力阻止肿瘤与其微环境之间的串扰，从而改善肿瘤的反应。
With a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat cancers such as pancreatic. Ref‐1 is a multifunctional protein with a role in redox signalling that activates transcription factors such as NF‐κB, AP‐1, HIF‐1α and STAT3. Formerly, we have demonstrated that dual targeting of Ref‐1 (redox factor‐1) and STAT3 is synergistic and decreases cell viability in pancreatic cancer cells. Data presented here extensively expands upon this work and provides further insights into the relationship of STAT3 and Ref‐1 in multiple cancer types. Using targeted small molecule inhibitors, Ref‐1 redox signalling was blocked along with STAT3 activation, and tumour growth evaluated in the presence and absence of the relevant tumour microenvironment. Our study utilized qPCR, cytotoxicity and in vivo analysis of tumour and cancer‐associated fibroblasts (CAF) response to determine the synergy of Ref‐1 and STAT3 inhibitors. Overall, pancreatic tumours grown in the presence of CAFs were sensitized to the combination of STAT3 and Ref‐1 inhibition in vivo. In vitro bladder and pancreatic cancer demonstrated the most synergistic responses. By disabling both of these important pathways, this combination therapy has the capacity to hinder crosstalk between the tumour and its microenvironment, leading to improved tumour response.
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影响因子：
5.7
作者：
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通讯作者：
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影响因子：
5.7
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Ciamporcero E;Shen H;Ramakrishnan S;Yu Ku S;Chintala S;Shen L;Adelaiye R;Miles KM;Ullio C;Pizzimenti S;Daga M;Azabdaftari G;Attwood K;Johnson C;Zhang J;Barrera G;Pili R
通讯作者：
Pili R
影响因子：
64.8
作者：
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通讯作者：
Grimmond, Sean M.