PubMed · 11157508
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D M Berwick. 2001-02-03. Not again!. https://doi.org/10.1136/bmj.322.7281.247
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TWIST, a basic helix-loop-helix transcription factor, has been reported to be associated with development and progression of human cancer. Recently, over expression of TWIST is found in cancer patients with shorter survival and poor response to chemotherapy. Previously, we found that upregulation of TWIST was responsible for the development of acquired resistance to taxol in a nasopharyngeal carcinoma (NPC) cell line, HNE1-T3 (Wang et al., Oncogene, 2004;24:274). In this study, we investigated the underlying molecular mechanisms responsible for the TWIST-mediated taxol resistance. By comparison of the parental HNE1 and its derivative HNE1-T3 cell lines, we found that the resistance to taxol in HNE1-T3 cells was associated with suppression of taxol-induced apoptosis evidenced by decreased expression of Bak and Bax and increased Bcl-2, as well as inhibition of PARP and caspase cleavage and DNA ladder formation. However, there was no correlation between taxol sensitivity and alterations on G2/M cell cycle distribution, suggesting that the TWIST-induced taxol resistance is mediated through protection against apoptosis but not mitotic arrest. Analysis of additional 8 NPC cell lines showed that upregulation of TWIST was associated with resistance to microtubule disrupting agents, especially taxol, and inactivation of TWIST through small RNA interference led to increased sensitivity to taxol-induced cell death. Subsequent studies also demonstrated that the TWIST-mediated taxol resistance may be regulated through its positive involvement with the Akt pathway. Our findings suggest an underlying molecular mechanism responsible for the TWIST-mediated chemodrug resistance and suggest a target for overcoming taxol resistance in cancer cells.
Epidemiological and preclinical evidence suggests that polyphenolic phytochemicals exemplified by epigallocatechin gallate from tea, curcumin from curry and soya isoflavones possess cancer chemopreventive properties. Whilst such naturally occurring polyphenols have been the subject of numerous mechanistic studies in cells, information on their clinical properties, which might help assess their promise as human cancer chemopreventive agents, is scarce. Therefore, we present a review of pilot studies and trials with a cancer chemoprevention-related rationale, in which either healthy individuals or patients with premalignant conditions or cancer received polyphenolic phytochemicals. The review identifies trial design elements specifically applicable to polyphenolic phytochemicals. The available evidence for tea polyphenols tentatively supports their advancement into phase III clinical intervention trials aimed at the prevention of progression of prostate intraepithelial neoplasia, leukoplakia or premalignant cervical disease. In the case of curcumin and soya isoflavones more studies in premalignacies seem appropriate to optimise the nature and design of suitable phase III trials. The abundance of flavonoids and related polyphenols in the plant kingdom makes it possible that several hitherto uncharacterised agents with chemopreventive efficacy are still to be identified, which may constitute attractive alternatives to currently used chemopreventive drugs.
Paclitaxel plays an important role in the treatment of primary breast cancer. However, a substantial proportion of patients treated with paclitaxel does not appear to derive any benefit from this therapy. We performed a prospective study using tumour cells isolated from 50 primary breast carcinomas. Sensitivity of primary tumour cells to paclitaxel was determined in a clinically relevant range of concentrations (0.85-27.2 microg ml(-1) paclitaxel) using an ATP assay. Chemosensitivity data were used to study a possible association with immunohistochemically determined oestrogen and progesterone receptor (ER and PR) status, as well as histopathological parameters. Progesterone receptor (PR) mRNA expression was also determined by quantitative RT-PCR. We observed a clear association of the PR status with chemosensitivity to paclitaxel. Higher levels of immunohistochemically detected PR expression correlated with decreased chemosensitivity (P=0.008). Similarly, high levels of PR mRNA expression were associated with decreased paclitaxel chemosensitivity (P=0.007). Cells from carcinomas with T-stages 3 and 4 were less sensitive compared to stages 1 and 2 (P=0.013). Multiple regression analysis identified PR receptor status and T-stage as independent predictors of paclitaxel chemosensitivity, whereas the ER, N-stage, grading and age were not influential. In conclusion, in vitro sensitivity to paclitaxel was higher for PR-negative compared with PR-positive breast carcinoma cells. Thus, PR status should be considered as a possible factor of influence when designing new trials and chemotherapy protocols.