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Molecular and chemical targets for tumor-selective cancer treatment

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Traditional anti-cancer drugs target the proliferative advantage of tumor cells over normal cells. This kind of approach lacks the selectivity of treatment to cancer cells, because most pathways targeted are essential for the survival of normal cells. As a result, traditional cancer treatment is often limited ...

Traditional anti-cancer drugs target the proliferative advantage of tumor cells over normal cells. This kind of approach lacks the selectivity of treatment to cancer cells, because most pathways targeted are essential for the survival of normal cells. As a result, traditional cancer treatment is often limited by undesirable damages of normal cells (side-effects). Tumor-selective cancer treatment can be achieved by targeting pathways essential for the survival of cancer cells, but not normal cells.

As cancer cells are characterized by their resistance to apoptosis, tumor-selective induction of apoptosis is a promising approach for tumor-selective cancer treatment. Increasing body of evidence suggests that tumor-selective cytotoxicity can be achieved by diverse chemical, physical, and pharmacological approaches. For instance, several tumoricidal proteins of cellular and oncolytic virus origins such as tumor necrosis factor-related apoptosis ligand and apoptin induces apoptosis in a large panel of human tumor but not normal cells. Cancer-specific metabolism such as increased glycolysis (the Warburg effect), hypoxia, and acidity may contribute to the progression of malignant cell growth and resistance to chemotherapy. These pathways may serve as another potential target to achieve tumor-selective cytotoxicity.

Besides these well-characterized compounds, diverse naturally-occurring and synthetic compounds including wogonin, ATP-sensitive potassium channel inhibitors, garic organosulfur compounds, hydrogen peroxide and atmospheric plasma induce apoptosis in tumor cells, but not in normal cells. Killer lymphocytes and NK cells may be the primary “tumor-selective effector” in tumor immune surveillance. These cells trigger both caspase-dependent and -independent apoptosis by releasing granzyme serine proteases. Strikingly, reactive oxygen species (ROS) generation is a common event observed after the chemical and/or physical interventions described above. Intra-mitochondrial ROS, a major cause of mitochondrial integrity disruption, are shown to be a universal mediator of pro-apoptotic effects of several tumor-selective drugs. Moreover, recent evidence suggests that shifting the metabolism of cancer cells from glycolysis to mitochondrial glucose oxidation promotes mitochondrial ROS-mediated death pathways and suppress tumor growth and angiogenesis with high selectivity. In addition, cancer cells are shown to be more sensitive than normal cells to apoptosis induced by mitochondrial toxins such as rotenone and this becomes prominent under low glucose conditions. Collectively, these observations suggest that cancer cells are more vulnerable than normal cells to increased mitochondrial oxidative stress and hence mitochondrial ROS-generating compounds kill cancer cells selectively.

The aim of this Research Topic is to integrate our current understanding regarding this important field of cancer research in an attempt to establish the effectiveness of mitochondrial ROS-generating substances in tumor-selective apoptosis. We encourage original, perspectives, and review articles that relate to any aspect of tumor-selective induction of apoptosis. Topics include all genetic, pharmacological, and physical interventions that induce apoptosis in a tumor-selective manner. Crosstalk between ROS and other physiological factors regulating apoptosis, such as calcium, membrane potential change, pH, and oxygen tension are also an area of this Research Topic. Articles dealing with mechanisms of tumor-selective signaling pathways, metabolism, and biological responses are highly welcome.


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