Chapter 9: Metakaryotic Cancer Stem Cells are Constitutively Resistant to X-Rays and Chemotherapeutic Agents, but Sensitive to Many Common Drugs
Published:09 Aug 2016
E. V. Gostjeva, V. V. Koledova, L. Bai, K. C. Duan, T. Kamath, M. Nelson, ... W. G. Thilly, in Human Stem Cell Toxicology, ed. J. L. Sherley, The Royal Society of Chemistry, 2016, ch. 9, pp. 196-249.
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After radio- and chemo-therapy, human tumors display many dead eukaryotic cells with pyknotic nuclei. But amitotic metakaryotic cells with hollow, bell-shaped nuclei appear unaffected as expected of treatment-resistant cancer stem cells. These same phenomena may be observed in vitro using any of many tumor- or metastasis-derived cell lines, for which their immortality is conferred by the presence of amitotic, metakaryotic cancer stem cells. About 5% of human colonic adenocarcinoma-derived HT-29 cells in exponential growth are immortal metakaryotic stem cells that increase by symmetric amitoses and continuously create mortal mitotic eukaryotic cells by asymmetric amitoses. Two assays for agents/conditions lethal to metakaryotic stem cells have been devised: (1) microscopic recognition of necrotic metakaryotic nuclei; and (2) survival of cells forming large immortal colonies visibly containing metakaryotic stem cells in vitro. X-rays and chemotherapeutic agents (i.e., alkylating agents, antimetabolites, and mitocides) kill eukaryotic cells, but not metakaryotic cells, at doses commonly used in cancer therapy. In contradistinction, multiple classes of common drugs are preferentially cytotoxic to metakaryotic stem cells including NSAIDS, antibiotics, and drugs used to treat diabetes or hypertension. Given lesion penetration and treatments of sufficient duration, regimens using multiple metakaryocidal drugs offer means to treat and prevent cancers.