Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-α.
Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-α.
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DOI：
10.1016/j.biocel.2015.08.002
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
S. K. Hira;I. Mondal;D. Bhattacharya;K. Gupta;P. Manna
中科院分区：
文献类型：
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作者：
S. K. Hira;I. Mondal;D. Bhattacharya;K. Gupta;P. Manna
尽管有些人对此有争议，但越来越多的证据表明，肿瘤坏死因子-α与传统化疗药物具有协同作用，可以发挥更高的抗肿瘤作用。本研究观察了重组IL-15联合STAT3抑制剂葫芦素-I在阿霉素耐药小鼠淋巴瘤模型中的抗肿瘤效果。这项工作的意义在于了解和设计有效的治疗阿霉素耐药淋巴瘤的策略。肿瘤坏死因子-α在道尔顿淋巴瘤小鼠的树突状细胞中表达下调，并与疾病进展呈负相关。多柔比星耐药的DL细胞Bcl2和Mcl-1水平升高，STAT3磷酸化增加。这些细胞对树突状细胞来源的肿瘤坏死因子-α不耐药。多柔比星耐药的道尔顿淋巴瘤在STAT3抑制剂葫芦素-I的刺激下，易受树突状细胞来源的肿瘤坏死因子-α的影响，葫芦素-I下调STAT3和其他生存分子。小剂量葫芦素-I和rIL-15联合治疗对阿霉素耐药的道尔顿淋巴瘤小鼠无效，但类似的治疗延长了亲本道尔顿淋巴瘤移植小鼠的生存时间。多柔比星耐药的道尔顿淋巴瘤对大剂量葫芦素-I和rIL-15的治疗有反应。小鼠来源的树突状细胞对治疗反应积极，并在抑制和杀伤DL肿瘤细胞方面恢复了其杀瘤特性。与DL相似，慢性粒细胞白血病患者来源的DC表达肿瘤坏死因子-α，不能抑制耐药淋巴瘤和白血病细胞的生长。这种联合治疗方法可作为治疗侵袭性和高转移性阿霉素耐药淋巴瘤的新策略。
Although disputed by some, increasing evidence suggests that TNF-α synergies with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant IL-15 in combination with the STAT3 inhibitor cucurbitacin-I in a doxorubicin-resistant murine lymphoma model. The significance of the work is to understand and design effective strategies in doxorubicin resistant lymphomas. TNF-α is downregulated in dendritic cells from mice with Dalton's lymphoma and shows an inverse relationship with disease progression. Doxorubicin-resistant DL cells have elevated levels of Bcl-2 and Mcl-1 and increased phosphorylation of STAT3. These cells are refractory to dendritic cell derived TNF-α. Doxorubicin resistant Dalton's lymphoma is susceptible to dendritic cell derived TNF-α upon stimulation with the STAT3 inhibitor cucurbitacin-I, which downregulates STAT3 and other survival molecules. The combined treatment of low dose of cucurbitacin-I and rIL-15 is ineffective in mice with doxorubicin resistant Dalton's lymphoma, but a similar therapy prolongs the survival of mice transplanted with parental Dalton's lymphoma. Doxorubicin resistant Dalton's lymphoma responds to therapy with high doses of cucurbitacin-I and rIL-15. Dendritic cell derived from mice responded positively to the therapy and regained their tumoricidal properties with respect to growth inhibition and killing of DL tumor cells. Similar to DL, DC derived from CML patients are impaired in TNF-α expression and are unable to restrict the growth of drug-resistant lymphoma and leukemia cells. This combination approach could be used as a new therapeutic strategy for aggressive and highly metastatic doxorubicin resistant lymphoma.