- Email: [email protected]
A radical drug mechanism to inhibit tumor growth, metastasis, and resistance: Targeting lysosomal P-glycoprotein
M. Casal / Free Radical Biology and Medicine 120 (2018) S6–S23
L-50
A radical drug mechanism to inhibit tumor growth, metastasis, and resistance: Targeting lysosomal P-glycoprotein
S19
of cancer cells, metastasis, angiogenesis, tolerance to anticancer therapy, and self-renewal activity of stem-like cells.
E-mail address: [email protected]; [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.080
D.R. Richardson University of Sydney,Sydney, NSW, Australia
L-52
Multidrug resistance is a major obstacle in cancer treatment due to the ability of tumor cells to efflux drugs via transporters (e.g. P-glycoprotein (Pgp)). Although the mechanism of Pgp-mediated drug efflux is known at the plasma membrane, the functional role of intracellular Pgp is unclear. This investigation aimed to dissect the effects of tumor micro-environmental stress on Pgp expression, localization, and its role in MDR. These studies demonstrated that tumor micro-environment stressors induce Pgp-mediated drug resistance. This occurred by two mechanisms, where stressors induced: 1) rapid Pgp internalization and redistribution (within 1 h) and 2) hypoxia-inducible factor-1α expression after longer incubations (4–24 h), which upregulated Pgp and was accompanied by lysosomal biogenesis. These two mechanisms increased lysosomal Pgp and facilitated lysosomal accumulation of the Pgp substrate, doxorubicin, resulting in resistance. This was consistent with lysosomal Pgp transporting substrates into lysosomes. When stress stimuli increased lysosomal accumulation of the cytotoxic Pgp substrate, di-2pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), this resulted in the agent overcoming resistance. As such, a novel approach to overcoming resistance will be discussed.
Ferroptosis in carcinogenesis and tumor biology
E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.079
Shinya Toyokuni Nagoya University Graduate School of Medicine, Nagoya, Japan
Excess iron is associated with carcinogenesis. Ferric nitrilotriacetateinduced renal cancers in wild-type rats reveal similar genetic alterations to those in humans. Ferroptosis may be defined as a form of regulated necrosis, characterized by lipid peroxidation through high iron/sulfur(antioxidants) ratio. Considering that cancer cells in general retain more catalytic Fe(II) than non-tumorous cells, many iron-induced carcinogenesis models, including asbestos-induced mesothelioma, suggest that cancer is a state of iron addiction with ferroptosis-resistance. Non-thermal plasma (NTP) is a novel physical technique that emits abundant electrons, leading to a variety of ROS products by reaction with atmospheric oxygen. Exposure of NTP to biomolecules, cells or tissues causes oxidative stress in situ, resulting in DNA breaks and lipid peroxidation products, such as HNE. We found that NTP exposure is highly dependent on Fe(II) in situ, causing cancer cell-specific ferroptosis, which was associated with autophagy activation and lysosome genesis. Thus, we discuss the role of phlebotomy for cancer prevention and the use of NTP as a new cancer therapy.
E-mail address: [email protected] L-51
Differential roles for the redox sensitive transcription factor Nrf2 in carcinogenesis
References Toyokuni S et al., FRBM 108: 610, 2017; Shi L et al., FRBM 108: 904, 2017; Stockwell BR, et al. Cell 171: 273, 2017.
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.081
Hoang-Kieu-Chi Ngo, Do-Hee Kim, Jinyoung Suh, Sin-Aye Park, Su Jung Kim, Soma Saeidi, Hye-Kyung Na, Young-Joon Surh Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
L-53
Autophagy and its link to the endoplasmic reticulum Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of a battery of genes encoding antioxidant and carcinogen detoxifying enzymes. In contrast to its tumor suppressive functions in normal cells, Nrf2 facilitates tumor growth and progression through metabolic reprograming in some cancer cells. Our previous study has demonstrated that 15-deoxy-Δ12,14-prostaglandin J2 and 4-hydroxyestradiol induce overactivation of Nrf2 and consequently overexpression of its target protein, heme oxygenase-1 (HO-1), in human breast cancer cells. More recently, we have demonstrated the involvement of Nrf2 in experimentally induced hepatocarcinogenesis (N.H.K. Chi et al., Cancer Res., 2017). In this context, the cellular stress response or cytoprotective signaling mediated via the Nrf2-HO1 axis is hijacked by cancer cells. This may facilitate the remodeling of the tumor microenvironment making it advantageous for the autonomic growth
Veit Goder Department of Genetics, University of Seville, Seville, Spain
Autophagy is a conserved cellular process characterized by the de novo generation of double-membraned autophagosomes. It plays a significant role in promoting survival during periods of starvation when the increased generation of autophagosomes leads to the enclosure of bulk cytosol and the transport to the vacuole/lysosome where the protein content is degraded down to amino acids for reuse. More recently it was found that autophagy is also vital in cellular quality control by removing
L-50
A radical drug mechanism to inhibit tumor growth, metastasis, and resistance: Targeting lysosomal P-glycoprotein
S19
of cancer cells, metastasis, angiogenesis, tolerance to anticancer therapy, and self-renewal activity of stem-like cells.
E-mail address: [email protected]; [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.080
D.R. Richardson University of Sydney,Sydney, NSW, Australia
L-52
Multidrug resistance is a major obstacle in cancer treatment due to the ability of tumor cells to efflux drugs via transporters (e.g. P-glycoprotein (Pgp)). Although the mechanism of Pgp-mediated drug efflux is known at the plasma membrane, the functional role of intracellular Pgp is unclear. This investigation aimed to dissect the effects of tumor micro-environmental stress on Pgp expression, localization, and its role in MDR. These studies demonstrated that tumor micro-environment stressors induce Pgp-mediated drug resistance. This occurred by two mechanisms, where stressors induced: 1) rapid Pgp internalization and redistribution (within 1 h) and 2) hypoxia-inducible factor-1α expression after longer incubations (4–24 h), which upregulated Pgp and was accompanied by lysosomal biogenesis. These two mechanisms increased lysosomal Pgp and facilitated lysosomal accumulation of the Pgp substrate, doxorubicin, resulting in resistance. This was consistent with lysosomal Pgp transporting substrates into lysosomes. When stress stimuli increased lysosomal accumulation of the cytotoxic Pgp substrate, di-2pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), this resulted in the agent overcoming resistance. As such, a novel approach to overcoming resistance will be discussed.
Ferroptosis in carcinogenesis and tumor biology
E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.079
Shinya Toyokuni Nagoya University Graduate School of Medicine, Nagoya, Japan
Excess iron is associated with carcinogenesis. Ferric nitrilotriacetateinduced renal cancers in wild-type rats reveal similar genetic alterations to those in humans. Ferroptosis may be defined as a form of regulated necrosis, characterized by lipid peroxidation through high iron/sulfur(antioxidants) ratio. Considering that cancer cells in general retain more catalytic Fe(II) than non-tumorous cells, many iron-induced carcinogenesis models, including asbestos-induced mesothelioma, suggest that cancer is a state of iron addiction with ferroptosis-resistance. Non-thermal plasma (NTP) is a novel physical technique that emits abundant electrons, leading to a variety of ROS products by reaction with atmospheric oxygen. Exposure of NTP to biomolecules, cells or tissues causes oxidative stress in situ, resulting in DNA breaks and lipid peroxidation products, such as HNE. We found that NTP exposure is highly dependent on Fe(II) in situ, causing cancer cell-specific ferroptosis, which was associated with autophagy activation and lysosome genesis. Thus, we discuss the role of phlebotomy for cancer prevention and the use of NTP as a new cancer therapy.
E-mail address: [email protected] L-51
Differential roles for the redox sensitive transcription factor Nrf2 in carcinogenesis
References Toyokuni S et al., FRBM 108: 610, 2017; Shi L et al., FRBM 108: 904, 2017; Stockwell BR, et al. Cell 171: 273, 2017.
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.081
Hoang-Kieu-Chi Ngo, Do-Hee Kim, Jinyoung Suh, Sin-Aye Park, Su Jung Kim, Soma Saeidi, Hye-Kyung Na, Young-Joon Surh Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
L-53
Autophagy and its link to the endoplasmic reticulum Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of a battery of genes encoding antioxidant and carcinogen detoxifying enzymes. In contrast to its tumor suppressive functions in normal cells, Nrf2 facilitates tumor growth and progression through metabolic reprograming in some cancer cells. Our previous study has demonstrated that 15-deoxy-Δ12,14-prostaglandin J2 and 4-hydroxyestradiol induce overactivation of Nrf2 and consequently overexpression of its target protein, heme oxygenase-1 (HO-1), in human breast cancer cells. More recently, we have demonstrated the involvement of Nrf2 in experimentally induced hepatocarcinogenesis (N.H.K. Chi et al., Cancer Res., 2017). In this context, the cellular stress response or cytoprotective signaling mediated via the Nrf2-HO1 axis is hijacked by cancer cells. This may facilitate the remodeling of the tumor microenvironment making it advantageous for the autonomic growth
Veit Goder Department of Genetics, University of Seville, Seville, Spain
Autophagy is a conserved cellular process characterized by the de novo generation of double-membraned autophagosomes. It plays a significant role in promoting survival during periods of starvation when the increased generation of autophagosomes leads to the enclosure of bulk cytosol and the transport to the vacuole/lysosome where the protein content is degraded down to amino acids for reuse. More recently it was found that autophagy is also vital in cellular quality control by removing