Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27

Abstract

BACKGROUND: In the current study, the authors sought to identify the molecular mechanisms underlying the chemoresistance of lung cancer stem or initiation cells (cancer stem cells). METHODS: A549 lung cancer cells before and after selective enrichment of a subpopulation of cancer stem cells were treated with superoxide and traditional chemotherapeutics to determine their sensitivity or resistance to these cytotoxic agents. Apoptotic activity was measured using a variety of fluorescence‐based and biochemical techniques. Specific pathways involved in the chemoresistance of cancer stem cell‐enriched lung cancer cells were analyzed with Western blotting and pharmacologic targeting therapy in a xenograft model. RESULTS: Lung cancer stem cells exhibited significantly decreased apoptotic response to treatment with superoxide, cisplatin, gemcitabine, or a combination of cisplatin and gemcitabine compared with control A549 cells. Apoptotic resistance was mediated through the inactivation of caspase‐9 and caspase‐3. Increased activation of p38MAPK, MAPKAPK2, and Hsp27 was observed in lung cancer stem cells compared with control A549 cells both before and after exposure to superoxide and chemotoxic agents. In a mouse model of lung cancer, chemotherapy‐induced cells increased in the antiapoptosis pathway, and quercetin, an inhibitor of Hsp27, combined with traditional chemotherapy was effective in blocking the pathway and in the treatment of lung tumors in vivo. CONCLUSIONS: The authors' data demonstrate that lung cancer stem cells have elevated levels of activated Hsp27 upon treatment with superoxide and traditional chemotherapy. When combined with chemotoxic agents, blockage of Hsp27 decreased the survival of lung cancer stem cells, which otherwise were resistant to traditional chemotherapy. Cancer 2011. © 2010 American Cancer Society.

Therapeutic strategies targeting cancer stem cells

“…40 In addition to having synergistic effects with sulforaphane, quercetin, combined with chemotherapeutic drugs, is effective in blocking antiapoptosis pathway of lung CSCs. 41 Curcumin, a popular food spice, can inhibit the SP phenotype of the rat C6 glioma cell line, 42 and berberine, a quaternary ammonium salt from the protoberberine, can suppress the self-renewal of SP cells and ABCG2 transporter expression in human MCF-7 breast cancer cells. 43 Gamma-tocotrienols (gamma-T3), one of the vitamin-E constituents, can inhibit the tumorigenicity of prostate cancer cells and kill docetaxel-resistant CD133-enriched PC-3 prostate cancer cells.…”

In vitro and in vivo evaluation of tubulin inhibitors with non-small cell lung cancer pre-clinical models

“…A small (27 kDa) member of this family, Hsp27, is well established to be particularly adept at protecting cancer cells from various anti-cancer therapeutic agents [12]. Such protection is conferred by enhanced proliferation [11,13] and suppressed apoptosis in cancer cells [14][15][16]. Increased expression of Hsp27 is found in various cancer types [9,10,[17][18][19][20][21], supporting the hypothesis that Hsp27 is a therapeutic target in a broad spectrum of cancers.…”

“…Heat shock proteins (Hsp) have been shown to be significantly elevated in cancers, and have been associated with cancer progression and drug resistance [9][10][11]. A small (27 kDa) member of this family, Hsp27, is well established to be particularly adept at protecting cancer cells from various anti-cancer therapeutic agents [12].…”

Flavonoides como agentes quimiopreventivos y terapéuticos contra el cáncer de pulmón

“…En la tabla 2 se presenta un resumen de los principales estudios realizados en modelos celulares y animales al respecto 51,52,[54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70] . Un estudio in vivo con ratones a los que se induce cáncer mediante la molécula benzo(a)pireno, presente en el humo del tabaco, muestra la capacidad de la fisetina, un flavonol presente en frutas y hortalizas (fresa, manzana, caqui, uva, cebolla y pepino), para inhibir la proliferación celular y el desarrollo de tumores, gracias a sus propiedades antioxidantes 68 .…”