PubMed · 9427280
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H Pinedo. 1997. Future perspectives.. https://pubmed.ncbi.nlm.nih.gov/9427280/
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Activation of the apoptosis program has been implicated in the response of cancer cells to chemotherapy. Therefore, we postulated that chemotherapy-resistant prostate cancer has developed a lesion in the apoptosis signal transduction cascade. In this study, we investigated the mechanism underlying the resistance of apoptosis-insensitive prostate cancer cells to apoptosis. We approached this by comparing the response of the androgen-sensitive LNCaP cell line and the androgen-insensitive PC3 cell line to treatment with the topoisomerase I inhibitor, camptothecin. We demonstrated that LNCaP cells are susceptible to camptothecin-induced cell death, and PC3 cells are resistant. Additional studies confirmed that the mode of cell death in the LNCaP cells was by apoptosis. We then determined that a component of the resistance to death in the apoptosis-insensitive cells involved a defect in the generation of ceramide, a key lipid mediator of apoptosis. Specifically, we demonstrated that PC3 cells are unable to elevate ceramide in response to treatment with camptothecin. In contrast, elevations in ceramide levels occur in LNCaP cells in response to the same treatment. Significantly, additional studies showed that treatment with exogenous ceramide overcomes the lesion in the PC3 cells and induces apoptosis. In attempting to gain preliminary insight into the nature of the lesion in ceramide formation in the apoptosis-resistant cells, we established that generation of ceramide in LNCaP cells is independent of the de novo pathway. These studies present novel insights into the mechanism by which prostate cancer cells may be resistant to induction of apoptosis. The significance of this study lies in the fact that an understanding of the biological and molecular events contributing to the resistance of prostate cancer to therapy is crucial to the development of more effective regimens for advanced disease.
The bacterial cytolethal distending toxin (CDT) was previously shown to arrest the tumor-derived HeLa cell line in the G2-phase of the cell cycle through inactivation of CDK1, a cyclin-dependent kinase whose state of activation determines entry into mitosis. We have analysed the effects induced in HeLa cells by CDT, in comparison to those induced by etoposide, a prototype anti-tumoral agent that triggers a G2 cell cycle checkpoint by inducing DNA damage. Both CDT and etoposide inhibit cell proliferation and induces the formation of enlarged mononucleated cells blocked in G2. In both cases, CDK1 from arrested cells could be reactivated both in vitro by dephosphorylation by recombinant Cdc25B phosphatase and in vivo by caffeine. However, the cell cycle arrest triggered by CDT, unlike etoposide, did not originate from DNA strand breaks as demonstrated in the single cell gel electrophoresis assay and by the absence of slowing down of S phase in synchronized cells. Together with additional observations on synchronized HeLa cells, our results suggest that CDT triggers a G2 cell cycle checkpoint that is initiated during DNA replication and that is independent of DNA damage.
Analysis of the 1H NMR data of paclitaxel in comparison with its oxetane ring-opened analogue D-secopaclitaxel suggests that the oxetane moiety (D-ring) of paclitaxel serves as a conformational lock for the diterpene moiety and the C13 side chain.