Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice.
Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice.
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DOI：
10.18632/oncotarget.3834
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发表时间：
2015-06-30
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影响因子：
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通讯作者：
Lokeshwar BL
中科院分区：
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作者：
Zhang L;Shamaladevi N;Jayaprakasha GK;Patil BS;Lokeshwar BL
来自可食用植物的生物活性化合物在治疗晚期癌症方面疗效有限，但它们有可能提高联合治疗中化疗药物的疗效。多香果 (Pimenta dioica) 浆果的水提取物有望成为联合治疗或化学预防的候选药物之一。在体外和体内测试了多香果水提取物 (AAE) 对抗人乳腺癌 (BrCa) 细胞的效果。 AAE 降低了几种类型 BrCa 细胞的活力和克隆生长 (IC50 ≤ 100 μg/ml)，对非致瘤静止细胞的毒性有限 (IC50 >200 μg/ml)。 AAE 在 BrCa 中诱导的细胞毒性与细胞凋亡不一致，但与自噬标记物 LC3B 和 LC3B 阳性斑点水平升高相关。沉默自噬相关基因 (ATG) 的表达可防止 AAE 诱导的细胞死亡。此外，AAE 会抑制 Akt/mTOR 信号传导，并与化疗药物和 mTOR 信号传导抑制剂雷帕霉素联合使用时显示出增强的细胞毒性。如果在肿瘤植入后对小鼠进行灌胃，则对植入 MDA-MB231 肿瘤的无胸腺小鼠口服（灌胃）AAE 会轻微抑制肿瘤生长，但不显着（平均下降约 14%，p ≥ 0.20）。当小鼠预先服用 AAE 两周时，肿瘤生长显示出肿瘤可触知性和生长速度（达到肿瘤体积≥ 1,000 mm3 的时间）显着延迟（38%）。肿瘤组织分析显示，AAE 治疗的肿瘤中 LC3B 水平增加，表明治疗小鼠体内自噬性肿瘤细胞死亡增加。这些结果证明了 AAE 对 BrCa 的抗肿瘤和化学预防活性以及作为 mTOR 抑制佐剂的潜力。
Bioactive compounds from edible plants have limited efficacy in treating advanced cancers, but they have potential to increase the efficacy of chemotherapy drugs in a combined treatment. An aqueous extract of berries of Pimenta dioica (Allspice) shows promise as one such candidate for combination therapy or chemoprevention. An aqueous extract of Allspice (AAE) was tested against human breast cancer (BrCa) cells in vitro and in vivo. AAE reduced the viability and clonogenic growth of several types of BrCa cells (IC50 ≤ 100 μg/ml) with limited toxicity in non-tumorigenic, quiescent cells (IC50 >200 μg/ml). AAE induced cytotoxicity in BrCa was inconsistent with apoptosis, but was associated with increased levels of autophagy markers LC3B and LC3B-positive puncta. Silencing the expression of autophagy related genes (ATGs) prevented AAE-induced cell death. Further, AAE caused inhibition of Akt/mTOR signaling, and showed enhanced cytotoxicity when combined with rapamycin, a chemotherapy drug and an inhibitor of mTOR signaling. Oral administration (gavage) of AAE into athymic mice implanted with MDA-MB231 tumors inhibited tumor growth slightly but not significantly (mean decrease ~ 14%, p ≥ 0.20) if mice were gavaged post-tumor implant. Tumor growth showed a significant delay (38%) in tumor palpability and growth rate (time to reach tumor volume ≥ 1,000 mm3) when mice were pre-dosed with AAE for two weeks. Analysis of tumor tissues showed increased levels of LC3B in AAE treated tumors, indicating elevated autophagic tumor cell death in vivo in treated mice. These results demonstrate antitumor and chemo-preventive activity of AAE against BrCa and potential for adjuvant to mTOR inhibition.