Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer.
Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer.
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DOI：
10.1158/1940-6207.capr-14-0177
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发表时间：
2014-11
期刊：
影响因子：
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通讯作者：
Nangia-Makker P
中科院分区：
文献类型：
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作者：
Vasudevan A;Yu Y;Banerjee S;Woods J;Farhana L;Rajendra SG;Patel A;Dyson G;Levi E;Maddipati KR;Majumdar AP;Nangia-Makker P
越来越多的证据支持这样的论点，即许多恶性肿瘤，包括散发性结直肠癌（CRC），是由自我更新的、化疗耐药的癌症干细胞/干细胞样细胞（CSC/CSLC）驱动的，这强调了需要改进针对CSC/CSLC的预防和治疗策略。ω-3多不饱和脂肪酸（ω-3 PUFA）已被报道可抑制原发性肿瘤的生长，但其作为复发性癌症预防剂的潜力尚未开发。本研究的主要目的是检查二十碳五烯酸（EPA; ω-3 PUFA之一）是否与结肠癌化疗的支柱FuOx（5-FU+奥沙利铂）协同作用，以及（B）EPA本身或与常规化疗组合是否通过消除/抑制CSC/CSLC来预防结肠癌的复发。本研究使用了在CSC中高度富集的FuOx抗性（化学抗性; CR）结肠癌细胞。虽然EPA单独是有效的，但EPA和FuOx的组合在以下方面更有效：（a）抑制细胞生长、结肠球形成和球形成频率，（B）增加球崩解，（c）抑制CR结肠癌细胞的SCID小鼠异种移植物的生长，和（d）减少小鼠中的促炎代谢物。此外，EPA + FuOx导致CSC/CSLC群体减少。该方案的生长减少是细胞凋亡增加的结果，如PARP裂解所证明的。此外，增加的pPTEN、减少的pAkt、通过EPA使β-连环蛋白表达、定位和转录活性正常化表明PTEN/Akt轴和Wnt信号传导在调节该过程中的作用。我们的数据表明，EPA本身或与FuOx联合使用可能是CRC复发的有效预防策略。
Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer (CRC), are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs) underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is un-explored. The primary objectives of this investigation are to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (b) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemo-resistant; CR) colon cancer cells, highly enriched in CSCs, were utilized for this study. While EPA alone was effective, combination of EPA and FuOx was more potent in (a) inhibiting cell growth, colonosphere formation and sphere-forming frequency, (b) increasing sphere disintegration, (c) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (d) decreasing pro-inflammatory metabolites in mice. Additionally, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization and transcriptional activity by EPA suggests a role for PTEN/Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring CRC.