Reactive Oxygen Species‐Mediated Mechanisms of Action of Targeted Cancer Therapy

Teppo, Hanna‐Riikka; Soini, Ylermi; Karihtala, Peeter

doi:10.1155/2017/1485283

Cited by 137 publications

(101 citation statements)

References 92 publications

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“…A mild increase in ROS can lead to an adaptive survival response, including expression of NRF2 to increase GSH production, whereas a severe increase in ROS can trigger apoptosis. Hence, it has been recognized for some time that cancer cells are potentially vulnerable to treatments that enhance ROS levels and cause cell death (Trachootham et al, 2009;Kim et al, 2016;Chio and Tuveson, 2017;Teppo et al, 2017;Moloney and Cotter, 2018). Several strategies have been employed to induce ROS, including ionizing radiation, inhibition of the ubiquitin-proteasome pathway, and perturbing GSH, glucose, and glutamine metabolism (Gorrini et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Zarei

Nassar

et al. 2019

Journal of Experimental Medicine

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Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/− mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.

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Section: Discussionmentioning

confidence: 99%

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Zarei

Nassar

et al. 2019

Journal of Experimental Medicine

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“…Regarding metastatic ccRCC, several targeted therapies against VEGF have been approved, including sorafenib, sunitinib, pazopanib and axitinib [1]. Recently, it has been shown that some of these drugs also affect cellular redox homeostasis, beside their primary antitumor role [48]. In contrast to sorafenib, which shows prooxidant effects by a decrease in GSH level [49], sunitinib exhibits antioxidant effects via increase in GSH level and inhibition of neuronal nitric oxide synthase activity (NOS) [50].…”

Section: Discussionmentioning

confidence: 99%

GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients

Radić

Ćorić

Bukumirić

et al. 2019

Cancers

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Omega class glutathione transferases, GSTO1-1 and GSTO2-2, exhibit different activities involved in regulation of inflammation, apoptosis and redox homeostasis. We investigated the the prognostic significance of GSTO1 (rs4925) and GSTO2 (rs156697 and rs2297235) polymorphisms in clear cell renal cell carcinoma (ccRCC) patients. GSTO1-1 and GSTO2-2 expression and phosphorylation status of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ /mammalian target of rapamycin (mTOR) and Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathways in non-tumor and tumor ccRCC tissue, as well as possible association of GSTO1-1 with signaling molecules were also assessed. GSTO genotyping was performed by quantitative PCR in 228 ccRCC patients, while expression and immunoprecipitation were analyzed by Western blot in 30 tissue specimens. Shorter survival in male carriers of GSTO1*C/C wild-type genotype compared to the carriers of at least one variant allele was demonstrated (p = 0.049). GSTO1*C/C genotype independently predicted higher risk of overall mortality among male ccRCC patients (p = 0.037). Increased expression of GSTO1-1 and GSTO2-2 was demonstrated in tumor compared to corresponding non-tumor tissue (p = 0.002, p = 0.007, respectively), while GSTO1 expression was correlated with interleukin-1β (IL-1β)/pro-interleukin-1β (pro-IL-1β) ratio (r = 0.260, p = 0.350). Interaction of GSTO1 with downstream effectors of investigated pathways was shown in ccRCC tumor tissue. This study demonstrated significant prognostic role of GSTO1 polymorphism in ccRCC. Up-regulated GSTO1-1 and GSTO2-2 in tumor tissue might contribute to aberrant ccRCC redox homeostasis.

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“…For ROS generation by DKP-073, NOX enzymes may be involved as suggested by two used NOX inhibitors. The critical role of ROS in apoptosis regulation in melanoma cells was also seen, when other therapeutic strategies were applied, as chemotherapy and radiotherapy, 48 elesclomol, 49 PI3K inhibition, 12 or BRAF inhibition. 11…”

Section: Discussionmentioning

confidence: 95%

Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP‐073 in melanoma cells

Zhivkova

Kiecker

Langer

et al. 2018

Molecular Carcinogenesis

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Melanoma represents a prime example demonstrating the success of targeted therapy in cancer. Nevertheless, it remained a deadly disease until now, and the identification of new, independent strategies as well as the understanding of their molecular mechanisms may help to finally overcome the high mortality. Both indirubins and TNF‐related apoptosis‐inducing ligand (TRAIL) represent promising candidates. Here, the indirubin derivative DKP‐073 is shown to trigger apoptosis in melanoma cells, which is enhanced by the combination with TRAIL and is accompanied by complete loss of cell viability. Addressing the signaling cascade, characteristic molecular steps were identified as caspase‐3 activation, downregulation of XIAP, upregulation of p53 and TRAIL receptor 2, loss of mitochondrial membrane potential, and STAT‐3 dephosphorylation. The decisive step, however, turned out to be the early production of ROS already at 1 h. This was proven by antioxidant pretreatment, which completely abolished apoptosis induction and loss of cell viability as well as abrogated all signaling effects listed above. Thus, ROS appeared as upstream of all proapoptotic signaling. The data indicate a dominant role of ROS in apoptosis regulation, and the new pathway may expose a possible Achilleś heel of melanoma.

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Reactive Oxygen Species‐Mediated Mechanisms of Action of Targeted Cancer Therapy

Cited by 137 publications

References 92 publications

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients

Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP‐073 in melanoma cells

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