Cigarette Smoke Promotes Drug Resistance and Expansion of Cancer Stem Cell-Like Side Population

Abstract

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.

Nicotine Induces Tumor Growth and Chemoresistance through Activation of the PI3K/Akt/mTOR Pathway in Bladder Cancer

“…Recent studies reported that various cancer cells acquired chemoresistance toward anticancer drugs by cigarette smoke condensate (CSC) or nicotine. An and colleagues reported that Akt activated by CSC induced doxurbicin resistance in lung cancer cells (39). Furthermore, in lung cancer, it was reported that nicotine induced antiapoptotic effects and cellular proliferative effects through the PI3K/Akt pathway (16,18).…”

Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3

“…Moreover, expression of TWIST1 modulated by STAT3 enriched SP in MCF-7 cells. Drug- or chemo-resistance is also positively correlated with nicotine or cigarette smoke in many cancers [5, 10, 59–61]. For example, nicotine-induced chemo-resistance in non-small cell lung cancer (NSCLC) occurs through up-regulation of XIAP and surviving [5].…”

Prognostic Impact of Cigarette Smoking on the Survival of Patients with Established Nasopharyngeal Carcinoma

“…Furthermore, tumor hypoxia has been acknowledged to affect the responses to both radiotherapy (38) and chemotherapy (39), and has been associated with poorer OS in HNSCC (40). In addition, basic research has demonstrated that cigarette smoke condensate promotes chemoresistance via Akt-mediated regulation of the activity of the ATP-binding cassette transporter G2, and may also contribute to tumor recurrence, invasion, or metastasis by increasing the proportion of cancer stem-like cells (41). Thus, the presence of residual smoke condensate in former and current smokers may reduce the effect of chemotherapy and promote tumor progression.…”

“…Finally, a recent study (42) found that 13% of cancer patients who did not smoke in the 7 days before surgery had resumed smoking within 12 months after surgery; their resumption of smoking was related to a higher perceived difficulty of quitting and lower perceptions of their cancer-related risk. Research has shown that continued smoking after diagnosis has immediate adverse impacts, including reduced efficacy of cancer treatment (5,41), increased proportions of cancer stem-like cells (41), higher rates of treatment complications and side effects (43,44), higher treatment-related weight loss (45), and a poorer quality of life (46). Unfortunately, we did not collect data on the patients who resumed or continued smoking during treatment or follow-up in this study; therefore, the possibility that some former smokers resumed smoking during treatment or follow-up cannot be ignored.…”