Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance

Chun, Kyung‐Soo; Kim, Do-Hee; Surh, Young‐Joon

doi:10.3390/cells10040758

Cited by 31 publications

(17 citation statements)

References 128 publications

(90 reference statements)

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“…On the one hand, there is an urgent need to explore novel active species other than ROS/RNS, such as alkyl radicals (Rc) 104,105 or chlorine radicals (cCl), 106 which may exhibit higher efficacy in tumor treatment. On the other hand, reductive stress attracts increasing attention, 107 which could break through the bottleneck of existing oxidative stress-mediated tumor treatment.…”

Section: Discussionmentioning

confidence: 99%

Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry

et al. 2022

Chem. Sci.

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Section: Discussionmentioning

confidence: 99%

Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry

et al. 2022

Chem. Sci.

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“…Redox homeostasis -a balance between cellular oxidants and antioxidants with reductive potential -is essential for the maintenance of normal physiological functions but also plays an important role in growth, survival, and therapy resistance of cancer cells (Chun et al, 2021).…”

Section: Hypoxia Acidosis and Oxidative Stress: Roles Of Tme Selectio...mentioning

confidence: 99%

“…On the other hand, when ROS concentrations become extremely high, they cause tumor cell death. A mild and persistent oxidative stress induced by chemotherapy induces adaptive stress responses with consequently excessive accumulation/production of reductive molecules, which may stimulate survival, resistance to chemotherapy, and stemness of tumor cells (Chun et al, 2021). This fact suggests that tumors shift their TME to more reductive conditions by adapting to the ROS threshold in response to chemotherapy.…”

Section: Hypoxia Acidosis and Oxidative Stress: Roles Of Tme Selectio...mentioning

confidence: 99%

Impact of cancer metabolism on therapy resistance – Clinical implications

Gonçalves

Richiardone

Jorge

et al. 2021

Drug Resistance Updates

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“…The ROS generation from the redox cycling of DOX was found to be responsible for its cytotoxicity. However, the Nrf2 signalling pathway activation was reported as a chemoprotective mechanism against DOX and liable for its inclined resistance [141,142]. The DOX and AP-1 treatments also upregulated livin in the MCF7 cells, an IAP, and its surge may account for drug resistance and tumour progression [143].…”

Section: Apoptotic Proteome Profiler Array Analysis 251 Effects Of Ap-1 and Dox On Apoptotic Proteins Of The Mcf7 Cellsmentioning

confidence: 99%

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

Alsherbiny

Bhuyan

Radwan

et al. 2021

IJMS

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The combination of natural products with standard chemotherapeutic agents offers a promising strategy to enhance the efficacy or reduce the side effects of standard chemotherapy. Doxorubicin (DOX), a standard drug for breast cancer, has several disadvantages, including severe side effects and the development of drug resistance. Recently, we reported the potential bioactive markers of Australian propolis extract (AP−1) and their broad spectrum of pharmacological activities. In the present study, we explored the synergistic interactions between AP−1 and DOX in the MCF7 breast adenocarcinoma cells using different synergy quantitation models. Biochemometric and metabolomics-driven analysis was performed to identify the potential anticancer metabolites in AP−1. The molecular mechanisms of synergy were studied by analysing the apoptotic profile via flow cytometry, apoptotic proteome array and measuring the oxidative status of the MCF7 cells treated with the most synergistic combination. Furthermore, label-free quantification proteomics analysis was performed to decipher the underlying synergistic mechanisms. Five prenylated stilbenes were identified as the key metabolites in the most active AP−1 fraction. Strong synergy was observed when AP−1 was combined with DOX in the ratio of 100:0.29 (w/w) as validated by different synergy quantitation models implemented. AP−1 significantly enhanced the inhibitory effect of DOX against MCF7 cell proliferation in a dose-dependent manner with significant inhibition of the reactive oxygen species (p < 0.0001) compared to DOX alone. AP−1 enabled the reversal of DOX-mediated necrosis to programmed cell death, which may be advantageous to decline DOX-related side effects. AP−1 also significantly enhanced the apoptotic effect of DOX after 24 h of treatment with significant upregulation of catalase, HTRA2/Omi, FADD together with DR5 and DR4 TRAIL-mediated apoptosis (p < 0.05), contributing to the antiproliferative activity of AP−1. Significant upregulation of pro-apoptotic p27, PON2 and catalase with downregulated anti-apoptotic XIAP, HSP60 and HIF-1α, and increased antioxidant proteins (catalase and PON2) may be associated with the improved apoptosis and oxidative status of the synergistic combination-treated MCF7 cells compared to the mono treatments. Shotgun proteomics identified 21 significantly dysregulated proteins in the synergistic combination-treated cells versus the mono treatments. These proteins were involved in the TP53/ATM-regulated non-homologous end-joining pathway and double-strand breaks repairs, recruiting the overexpressed BRCA1 and suppressed RIF1 encoded proteins. The overexpression of UPF2 was noticed in the synergistic combination treatment, which could assist in overcoming doxorubicin resistance-associated long non-coding RNA and metastasis of the MCF7 cells. In conclusion, we identified the significant synergy and highlighted the key molecular pathways in the interaction between AP−1 and DOX in the MCF7 cells together with the AP−1 anticancer metabolites. Further in vivo and clinical studies are warranted on this synergistic combination.

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Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance

Cited by 31 publications

References 128 publications

Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry

Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry

Impact of cancer metabolism on therapy resistance – Clinical implications

Metabolomic Identification of Anticancer Metabolites of Australian Propolis and Proteomic Elucidation of Its Synergistic Mechanisms with Doxorubicin in the MCF7 Cells

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