Abstract
Microtubule (MT) inhibitors show anti-cancer activity in a wide range of tumors in vitro and demonstrate high clinical efficacy. To date they are routinely included into many chemotherapeutic regimens. While the mechanisms of MT inhibitors’ interactions with tubulin have been well-established, the relationship between their concentration and effect on neoplastic cells is not completely understood. The common notion is that tumor cells are most vulnerable during division and all MT inhibitors block them in mitosis and induce mitotic checkpoint-associated cell death. At the same time multiple evidence of more subtle effects of lower doses of MT inhibitors on cell physiology exist. The extent of efficacy of the low-dose MT inhibitor treatment and the mechanisms of resulting cell death currently present a critical issue in oncology. The prospect of MT inhibitor dose reduction is promising as protocols at higher concentration have multiple side effects. We assessed cell cycle changes and cell death induced by MT inhibitors (paclitaxel, nocodazole, and vinorelbine) on human lymphoid B-cell lines in a broad concentration range. All inhibitors had similar accumulation effects and demonstrated “trigger” concentrations that induce cell accumulation in G2/M phase. Concentrations slightly below the “trigger” promoted cell accumulation in sub-G1 phase. Multi-label analysis of live cells showed that the sub-G1 population is heterogeneous and may include cells that are still viable after 24 h of treatment. Effects observed were similar for cells expressing Tat-protein. Thus cell cycle progression and cell death are differentially affected by high and low MT inhibitor concentrations.
Highlights
The importance of microtubule (MT) dynamics for cell motility (Liao et al, 1995), migration (Kaverina and Straube, 2011), and division (Jordan et al, 1993) has been well-established
We tested the mitostatic effect of three common stabilizing and depolymerizing MT inhibitors, on RPMI8866, RPMI8866-Tat-GFP (B-lymphocytes) and Jurkat (T-lymphocytes) cell lines
For 3 nM paclitaxel we observed 46% cells in G0/G1, 22% cells in S, and 18% in G2/M for RPMI8866 cells compared to 53% cells in G0/G1, 20% cells in S, and 18% in G2/M in control (Figure 1D)
Summary
The importance of microtubule (MT) dynamics for cell motility (Liao et al, 1995), migration (Kaverina and Straube, 2011), and division (Jordan et al, 1993) has been well-established. The multi-aspect effect of suppressed microtubule dynamics makes MT inhibitors an important part of most anti-cancer chemotherapeutic regimens by inhibiting tumor growth (antimitotic effect) and metastasis (antimigration effect) (Dumontet and Jordan, 2010). MT inhibitors of the first generation widely used in clinics (taxanes, vinca alkaloid derivatives) have certain drawbacks, including neurotoxic effects (Windebank, 1999), neutropenia (Donehower and Rowinsky, 1993) and loss of efficacy against advanced forms of some cancers (Sève et al, 2008). Varying effects of high and low MT inhibitor concentrations on different aspects of cell physiology have been described for a number of cell models (Grigoriev et al, 1999; Yang et al, 2010). The first meta-analysis focused on efficacy and toxicity of low-dose versus conventional-dose chemotherapies has been published recently (Xie et al, 2017) and provided data on low-dose chemotherapy advantages
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
