Cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population.
Cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population.
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DOI：
10.1371/journal.pone.0047919
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ongkeko WM
中科院分区：
文献类型：
--
作者：
An Y;Kiang A;Lopez JP;Kuo SZ;Yu MA;Abhold EL;Chen JS;Wang-Rodriguez J;Ongkeko WM
众所周知，许多患者在被诊断患有癌症后继续吸烟。虽然戒烟通常被认为对癌症几乎没有治疗价值，但越来越多的证据表明，继续吸烟与治疗效果降低和复发率升高有关。因此，我们研究了香烟烟雾冷凝物（CSC）对肺癌和头颈癌细胞系A549和USCC-10 B的耐药性的影响。我们的研究结果表明，CSC显着增加阿霉素和米托蒽醌的细胞外排。这伴随着膜定位和多药物转运蛋白ABCG 2的表达增加。在加入特异性ABCG 2抑制剂烟曲霉素C后，诱导的多柔比星外排逆转，证实了ABCG 2的作用。CSC治疗增加了磷酸化Akt的浓度，而加入PI 3 K抑制剂LY 294002阻断了阿霉素的外排，表明CSC诱导的药物外排需要Akt活化。此外，发现CSC促进对多柔比星的抗性，如通过MTS测定所确定的。这种CSC诱导的阿霉素耐药性被美加明（一种烟碱乙酰胆碱受体抑制剂）减轻，表明尼古丁至少部分地对CSC的作用负责。最后，CSC增加了侧群（SP）的大小，这与癌症干细胞样表型有关。总之，CSC通过Akt介导的ABCG 2活性调节促进化疗耐药性，并且还可能增加癌症干细胞样细胞的比例，从而有助于肿瘤的恢复。这些发现强调了癌症诊断后戒烟的重要性，并阐明了持续吸烟可能对治疗有害的机制。
It is well known that many patients continue to smoke cigarettes after being diagnosed with cancer. Although smoking cessation has typically been presumed to possess little therapeutic value for cancer, a growing body of evidence suggests that continued smoking is associated with reduced efficacy of treatment and a higher incidence of recurrence. We therefore investigated the effect of cigarette smoke condensate (CSC) on drug resistance in the lung cancer and head and neck cancer cell lines A549 and UMSCC-10B, respectively. Our results showed that CSC significantly increased the cellular efflux of doxorubicin and mitoxantrone. This was accompanied by membrane localization and increased expression of the multi-drug transporter ABCG2. The induced efflux of doxorubicin was reversed upon addition of the specific ABCG2 inhibitor Fumitremorgin C, confirming the role of ABCG2. Treatment with CSC increased the concentration of phosphorylated Akt, while addition of the PI3K inhibitor LY294002 blocked doxorubicin extrusion, suggesting that Akt activation is required for CSC-induced drug efflux. In addition, CSC was found to promote resistance to doxorubicin as determined by MTS assays. This CSC-induced doxurbicin-resistance was mitigated by mecamylamine, a nicotinic acetylcholine receptor inhibitor, suggesting that nicotine is at least partially responsible for the effect of CSC. Lastly, CSC increased the size of the side population (SP), which has been linked to a cancer stem cell-like phenotype. In summary, CSC promotes chemoresistance via Akt-mediated regulation of ABCG2 activity, and may also increase the proportion of cancer stem-like cells, contributing to tumor resilience. These findings underscore the importance of smoking cessation following a diagnosis of cancer, and elucidate the mechanisms of continued smoking that may be detrimental to treatment.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
4.8
作者：
Robinson, SN;Seina, SM;Sharp, JG
通讯作者：
Sharp, JG
影响因子：
4.7
作者：
Izzotti, Alberto;Larghero, Patrizia;De Flora, Silvio
通讯作者：
De Flora, Silvio
影响因子：
3.8
作者：
Matsunawa, Manabu;Amano, Yusuke;Makishima, Makoto
通讯作者：
Makishima, Makoto
早期肺癌诊断后戒烟对预后的影响：荟萃分析的观察性研究系统评价。
DOI：
10.1136/bmj.b5569
发表时间：
2010-01-21
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Parsons A;Daley A;Begh R;Aveyard P
通讯作者：
Aveyard P