The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer

Abstract

Parthenolide, a sesquiterpene lactone, shows antitumor activity in vitro, which correlates with its ability to inhibit the DNA binding of the antiapoptotic transcription factor nuclear factor KB (NF-KB) and activation of the c-Jun NH 2 -terminal kinase. In this study, we investigated the chemosensitizing activity of parthenolide in vitro as well as in MDA-MB-231 cell -derived xenograft metastasis model of breast cancer. HBL-100 and MDA-MB-231 cells were used to measure the antitumor and chemosensitizing activity of parthenolide in vitro. Parthenolide was effective either alone or in combination with docetaxel in reducing colony formation, inducing apoptosis and reducing the expression of prometastatic genes IL-8 and the antiapoptotic gene GADD45b1 in vitro. In an adjuvant setting, animals treated with parthenolide and docetaxel combination showed significantly enhanced survival compared with untreated animals or animals treated with either drug. The enhanced survival in the combination arm was associated with reduced lung metastases. In addition, nuclear NF-KB levels were lower in residual tumors and lung metastasis of animals treated with parthenolide, docetaxel, or both. In the established orthotopic model, there was a trend toward slower growth in the parthenolide-treated animals but no statistically significant findings were seen. These results for the first time reveal the significant in vivo chemosensitizing properties of parthenolide in the metastatic breast cancer setting and support the contention that metastases are very reliant on activation of NF-KB. [Mol Cancer Ther 2005;4(6):1004 -12]

NF-κB pathway inhibitors preferentially inhibit breast cancer stem-like cells

“…DETC, an analog of PDTC, also showed similar tumor growth inhibition effect in vivo as PDTC (data not shown). Our results are consistent with the previous finding that PTL in combination with docetaxel could reduce metastasis and improve survival in a xenograft model of breast cancer [59]. Taken together, this study indicates that it is possible to inhibit breast cancer stem cells by targeting the NF-κB pathway.…”

Assessment of apoptosis-inducing effects of docetaxel combined with the proteasome inhibitor PS-341 in human lung cancer cells

“…[3][4][5][6][7][8][9][10] The role of NFkB activation in taxane-induced apoptosis and therapy is still controversial. [3][4][5][6][8][9][10][11][12] However, most studies favor that NFkB activation contributes to taxane resistance and suppression of NFkB activation by various means sensitizes cancer cells to taxol-induced apoptosis.…”

Avaliação dos efeitos da subfração Acetato de etila III de Vemonia scorpioides em modelo de melanoma murino in vivo e in vitro

“…Nos tumores, a resistência às drogas é principalmente atribuída para o improvável reparo do DNA, provocando defeitos nos processos apoptóticos (ROZENBLAT et al, 2008 (KHALIL et al, 2005;SWEENEY et al, 2005;BUSKUHL, 2007).…”

“…Muitos desses compostos ou plantas contendo estes são as causas de dermatite alérgica de contato em humanos, porém muitos deles são bem usados por sua atividade farmacológica (PICMAN, 1986 Atualmente já sabemos que as sub-frações de Vernonia scorpioides e todas outras plantas da família Asteraceae contêm lactonas sesquiterpênicas, muitos são os estudos comprovando a atividade antitumoral destas moléculas, tanto in vitro com in vivo (KHALIL et al, 2005;SWEENEY et al, 2005;BUSKUHL, 2007).…”

“…Atualmente sabe-se que as sub-frações de Vernonia scorpioides e outras plantas da família Asteraceae contêm lactonas sesquiterpênicas, muitos são os estudos comprovando a atividade antitumoral destas moléculas, tanto in vitro com in vivo (TWARDOWSKI, 1979;KHALIL et al, 2005;SWEENEY et al, 2005;BUSKÜHL, 2007 Células de melanoma metastático são bem equipadas para resposta a estímulos inflamatórios e usa-os como vantagem para seu crescimento (MELNIKOVA et al, 2009). Melanoma é a forma de câncer de pele mais agressiva e é notória a sua resistência frente a todos os tipos de terapia para câncer já existente, apoptose é considerada o meio mais importante para a morte de células neoplásicas, porém deficiência relacionada a cascata de apoptose pode estar causando um fenótipo de resistência a quimioterapia (HELMBACH et al, 2001).…”