In addition, H 2 O 2 also depolymerizes microtubules 66 , which results in need for higher doses of Taxol to stabilize microtubules and induce cell death These effects may explain why hypoxia reduces toxicity to Taxol in cancer cells Figure 2.
Consequently, reducing ROS with antioxidants has long been proposed as a co-treatment to enhance the effects of Taxol, with some limited success The inconsistent results are likely due to the specific antioxidant used.
For example, the popular dietary antioxidants Resveratrol and Fisetin found in red wine , inhibit Cdks, induce a G2 arrest and prevent entry into mitosis 69 , 70 , providing an explanation for why they antagonize Taxol 71 , Therefore, finding methods that specifically reduce ROS without off target effects will be critical for the future success of co-treatment regimes.
Hypoxia can also cause depletion of ATP pools, however the mitotic effects of ATP depletion are opposite to that of hypoxia and oxidative stress. ATP is needed for microtubule disassembly 74 , and therefore depletion of ATP stabilizes microtubules In addition, depletion of ATP activates AMP-activated protein kinase, which phosphorylates myosin regulatory light chain, and promotes astral microtubule growth 76 Figure 2.
Surprisingly, depletion of ATP also depletes Mad2 and BubR1 from kinetochores, with both proteins accumulating at spindle poles, however this does not appear to affect their ability to bind Cdc20 and inhibit the APC 77 — Taken together, this area has significant potential for future novel therapeutic approaches, with some metabolic inhibitors already showing synergy with Taxol Heat-shock hyperthermia has been commonly used as adjunctive cancer therapy to augment radiotherapy and chemotherapy, with varying levels of success This delay is most likely SAC dependent due to effects on microtubules and centrosomes, which become permanently disorganized and destabilized upon exposure to heat Consequently, the mitotic delay is only temporary, and cells rapidly reform a nuclear envelope around chromosomes, and undergo mitotic slippage 86 , 87 , even in the presence of Taxol Hyperthermia has been shown to both antagonize 89 and synergize 88 with Taxol, with the outcome dependent on the functionality of the apoptotic pathway 90 , Interestingly, like hyperthermia, cold-shock hypothermia has also shown some success in synergizing with radiotherapy and a variety of chemotherapeutics 92 , Exposure to cold induces a transient mitotic delay in cells, however cells eventually complete mitosis and segregate their chromosomes normally Hypothermia reversibly destabilizes non-kinetochore microtubules 95 , 96 , but this still allows chromosomes to be captured by kinetochore microtubules and positioned at the metaphase plate However, a reduction in microtubule dynamics and loss of astral microtubules results in reduced tension at kinetochores leading to the retention of Bub1 and BubR1 at kinetochores and a SAC-dependent mitotic delay The ability of cells to recover from hypothermia and complete mitosis may explain why cold-shock can reduce the number of mitotic defects induced by chemotherapies 98 , and minimize side effects e.
However, given that the delay is transient and reversible, it also explains why co-treatment regimes have not shown any significant synergy and are unlikely to be useful for enhancing the killing of cancer cells.
As cells enter mitosis they transform their architecture to create a spherical shape, which is driven by changes in the actin cytoskeleton , and by regulation of osmotic pressure During early prophase RhoA promotes remodeling of the actin cytoskeleton, increasing the mechanical stiffness of the cell Cell rounding is achieved by combining RhoA-mediated cellular rigidity with increased hydrostatic pressure inside the cell.
This occurs by increasing intracellular sodium levels resulting in an influx of water Interestingly, placing cells in hypertonic solution preventing water influx stably arrests cells in mitosis and was originally used in the s as a method for enriching mammalian cells in mitosis After several hours most arrested cells die, although some escape via mitotic slippage to form polyploid cells Interestingly, in yeast, hypertonic stress can promote activation of Cdc14 phosphatase , which then dephosphorylates Cdk substrates driving cells out of mitosis, suggesting that phosphatases can drive slippage.
However, in humans the role of Cdc14 is not conserved , and PP2A appears to be the primary phosphatase responsible for removing mitotic Cdk1 phosphorylations , If PP2A is directly activated in response to hypertonic stress it could promote mitotic slippage in human cells, providing a rational for future research focusing on the effectiveness of PP2A inhibitors in combination with mitotic chemotherapies.
Exposure of mitotic cells to hypotonic conditions increases water influx, rising internal pressure and a swelling of mitotic cell size, with weak hypotonic solutions arresting cells in pro-metaphase However, unlike hypertonic stress, this arrest is far less stable and cells rapidly undergo mitotic slippage, characterized by chromosome decondensation, disrupted kinetochore and spindle structure, and reformation of the nuclear envelope around un-segregated chromosomes , , which all promote chromosome aberrations and polyploidy The effects of hypotonic stress in combination with Taxol have not been studied in detail, however, hypotonic solutions can increase the uptake of chemotherapies in cells , and have shown some promise in enhancing response to platinum-based treatments Consequently, it is likely that similar to hyperthermia, local hypotonic conditions could be used to enhance Taxol response in tumors with a functional apoptotic pathway.
In summary, the ability of cells to arrest during mitosis in response cellular and environmental stresses is dependent on the presence of a functional SAC, the correct suppression of transcription and translation, and critically the maintenance of Cdk1 activity.
Stress that prevents the satisfaction of the SAC results in a mitotic arrest, while those stresses that disrupt Cdk1 activity or directly disable the SAC force cells to prematurely exit mitosis. Future research on the role mitotic phosphatases, such as PP2A, play in stress response and slippage will be critical for fully elucidating the mechanisms of how a specific cancer will response or can be sensitized to mitotic chemotherapies such as Taxol.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank Dr. Liz Caldon, Ms. Rachael McCloy, and Dr. Andrew Stone for their helpful comments and advice. Sherr CJ. Cancer cell cycles. Science —7. Integrating stress-response and cell-cycle checkpoint pathways.
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