Cytosolic Cl- Affects the Anticancer Activity of Paclitaxel in the Gastric Cancer Cell Line, MKN28 Cell

Abstract

Background/Aims: Our previous study revealed that cytosolic Cl^- affected neurite elongation promoted via assembly of microtubule in rat pheochromocytoma PC12D cells and Cl^-–induced blockade of intrinsic GTPase enhanced tubulin polymerization in vitro. Paclitaxel (PTX) is a microtubule-targeted chemotherapeutic drug and stabilizes microtubules resulting in mainly blockade of mitosis at the metaphase-anaphase transition and induction of apoptosis. In the present study, we tried to clarify whether the cytosolic Cl^- affected PTX ability to inhibit cell growth in the gastric cancer cell line, MKN28. Methods: To clarify the cytosolic Cl^- action on PTX-induced cell death and metaphase-anaphase transition in the gastric cancer cell line, MKN28 cell, and PTX-induced tubulin polymerization, we performed cell proliferation assay, cytosolic Cl^- concentration measurement, immunofluorescence microscopy, and in vitro tubulin polymerization assay. Results: The decline of cytosolic Cl^- weakened the cytotoxic effect of PTX on cell proliferation of MKN28 cells, which could pass through the metaphase-anaphase transition. Moreover, in vitro PTX-induced tubulin polymerization was diminished under the low Cl^- condition. Conclusions: Our results strongly suggest that the upregulation of cytosolic Cl^- concentration would enhance the antitumor effect of PTX, and that the cytosolic Cl^- would be one of the key targets for anti-cancer therapy.

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

“…Bodily and cellular functions are controlled by various factors including ions such as Na + , K + , Ca 2+ , Mg 2+ , Zn 2+ , and Cl − [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. On the one hand, pH (−log[H + ]) is recognized as one of classical items considered to be already fully understood in roles and mechanisms of homeostasis.…”

Current-direction/amplitude-dependent single channel gating kinetics of mouse pannexin 1 channel: a new concept for gating kinetics

“…Replacement of extracellular Cl − with other anions induces a shift of the whole-cell current reversal potential and alters whole-cell current amplitudes: the anion selectivity sequence of mPanx1 channel has been reported to be NO 3 − > I − > Br − > Cl − > F − >> aspartate − ≈ glutamate − ≈ gluconate − 26 . Channel proteins such as acid-sensing ion channels (ASICs) 27 and epithelial Na + channel (ENaC) 28 have binding sites for Cl − , and activity of these channels is modulated by Cl − binding 27 , 28 , which plays essential roles in regulation of cell function 29 – 39 .…”

SKLB060 Reversibly Binds to Colchicine Site of Tubulin and Possesses Efficacy in Multidrug-Resistant Cell Lines

“…An important function of microtubules is to form spindles and separate sister chromosomes into two daughter cells during cell division to help complete cell division [3,[29][30][31]. Microtubule inhibitors can inhibit this process by destroying the microtubules.…”