bims-rehoca Biomed News
on Redox homeostasis in cancer
Issue of 2022–01–02
eight papers selected by
Vittoria Raimondi, Veneto Institute of Oncology
  1. Reactive Oxygen Species-Responsive Miktoarm Amphiphile for Triggered Intracellular Release of Anti-Cancer Therapeutics.
  2. CN-3 increases TMZ sensitivity and induces ROS-dependent apoptosis and autophagy in TMZ-resistance glioblastoma.
  3. Black cardamom (Amomum subulatum Roxb.) fruit extracts exhibit apoptotic activity against lung cancer cells.
  4. Effect of Alpha-tocopheryl Succinate on the Cytotoxicity of Anticancer Drugs Towards Leukemia Lymphocytes.
  5. A bis-pyridinium fullerene derivative induces apoptosis through the generation of ROS in BCR-ABL-positive leukemia cells.
  6. Overexpression of Reactive Oxygen Species Modulator 1 Predicts Unfavorable Clinical Outcome in EGFR-Mutant Lung Adenocarcinomas Treated With Targeted Therapy.
  7. Asbestos-induced mesothelial injury and carcinogenesis: Involvement of iron and reactive oxygen species.
  8. Development of cervical intraepithelial lesions and cervical cancer is not influenced by SOD2 RS4880 polymorhism.
  1. Polymers (Basel). 2021 Dec 16. pii: 4418. [Epub ahead of print]13(24):
    Reactive Oxygen Species-Responsive Miktoarm Amphiphile for Triggered Intracellular Release of Anti-Cancer Therapeutics.
    Hyun-Chul Kim, Eunjoo Kim, Se Guen Lee, Sung Jun Lee, Sang Won Jeong, Young Jae Lee, Mi Kyung Kwon, Seong-Kyoon Choi, Jun Seong Hwang, Eunsook Choi.
      Reactive oxygen species (ROS)-responsive nanocarriers have received considerable research attention as putative cancer treatments because their tumor cell targets have high ROS levels. Here, we synthesized a miktoarm amphiphile of dithioketal-linked ditocopheryl polyethylene glycol (DTTP) by introducing ROS-cleavable thioketal groups as linkers between the hydrophilic and hydrophobic moieties. We used the product as a carrier for the controlled release of doxorubicin (DOX). DTTP has a critical micelle concentration (CMC) as low as 1.55 μg/mL (4.18 × 10-4 mM), encapsulation efficiency as high as 43.6 ± 0.23% and 14.6 nm particle size. The DTTP micelles were very responsive to ROS and released their DOX loads in a controlled manner. The tocopheryl derivates linked to DTTP generated ROS and added to the intracellular ROS in MCF-7 cancer cells but not in HEK-293 normal cells. In vitro cytotoxicity assays demonstrated that DOX-encapsulated DTTP micelles displayed strong antitumor activity but only slightly increased apoptosis in normal cells. This ROS-triggered, self-accelerating drug release device has high therapeutic efficacy and could be a practical new strategy for the clinical application of ROS-responsive drug delivery systems.
    Keywords:  ROS-responsive; drug delivery system; miktoarm amphiphile; tocopheryl derivate; tumor therapy
    DOI:  https://doi.org/10.3390/polym13244418
  2. J Biochem Mol Toxicol. 2021 Dec 29. e22973
    CN-3 increases TMZ sensitivity and induces ROS-dependent apoptosis and autophagy in TMZ-resistance glioblastoma.
    Yu-Ye Xue, Yun-Yang Lu, Guang-Qiang Sun, Fei Fang, Yu-Qiang Ji, Hai-Feng Tang, Peng-Cheng Qiu, Guang Cheng.
      Many glioma patients develop resistance to temozolomide (TMZ) treatment, resulting in reduced efficacy and survival rates. TMZ-resistant cell lines SHG44R and U87R, which highly express O6 -methylguanine DNA methyltransferase (MGMT) and P-gp, were established. CN-3, a new asterosaponin, showed cytotoxic effects on TMZ-resistant cells in a dose- and time-dependent manner via reactive oxygen species (ROS)-mediated apoptosis and autophagy. Transmission electron microscopy and monodansylcadaverine (MDC) staining showed turgidity of the mitochondria and autophagosomes in CN-3-treated SHG44R and U87R cells. The autophagy inhibitor 3-methyladenine was used to confirm the important role of autophagy in CN-3 cytotoxicity in TMZ-resistant cells. The ROS scavenger N-acetyl- l-cysteine (NAC) attenuated the levels of ROS induced by CN-3 and, therefore, rescued the CN-3 cytotoxic effect on the viability of SHG44R and U87R cells by Cell Counting Kit-8 assays and JuLI-Stage videos. MDC staining also confirmed that NAC rescued an autophagosome increase in CN-3-treated SHG44R and U87R cells. Western blotting revealed that CN-3 increased Bax, cleaved-caspase 3, cytochrome C, PARP-1, LC3-Ⅱ, and Beclin1, and decreased P-AKT, Bcl-2, and p62. Further rescue experiments revealed that CN-3 induced apoptosis and autophagy through ROS-mediated cytochrome C, cleaved-caspase 3, Bcl-2, P-AKT, PARP-1, and LC3-Ⅱ. In addition, CN-3 promoted SHG44R and U87R cells sensitive to TMZ by reducing the expression of P-gp, MGMT, and nuclear factor kappa B p65, and it had a synergistic cytotoxic effect with TMZ. Moreover, CN-3 disrupted the natural cycle arrest and inhibited the migration of SHG44R and U87R cells by promoting cyclin E1 and D1, and by decreasing P21, P27, N-cadherin, β-catenin, transforming growth factor beta 1, and Smad2.
    Keywords:  ROS; TMZ; asterosaponin; glioblastoma; resistance; starfish Culcita novaeguineae
    DOI:  https://doi.org/10.1002/jbt.22973
  3. J Ethnopharmacol. 2021 Dec 27. pii: S0378-8741(21)01183-1. [Epub ahead of print] 114953
    Black cardamom (Amomum subulatum Roxb.) fruit extracts exhibit apoptotic activity against lung cancer cells.
    Pooja Makhija, Harish K Handral, Gomathi Mahadevan, Himanshu Kathuria, Gautam Sethi, Bert Grobben.
       ETHNOPHARMACOLOGICAL RELEVANCE: The dried fruits of Amomum subulatum Roxb. (A. subulatum) are widely used as a spice. It is a part of official ayurvedic formulations and it is used in folklore medicine to treat cancer.A. subulatum has been used in ayurvedic formulations to treat various lung conditions such as cough, lung congestion, pulmonary tuberculosis. The present traditional knowledge highlights the effectiveness of A. subulatum in treating cancer and its lung-specific efficacy.
    AIM OF THE STUDY: This study aims to investigate the cytotoxic potential of A. subulatum on the phenomenal and mechanistic level of lung cancer cells and identify the presence of A. subulatum actives.
    MATERIALS AND METHODS: The bioactivity of the extracts was tested using MTT assay, apoptotic assay, cell cycle analysis, superoxide production assay, reactive oxygen species (ROS) assay, and Western blot analysis. Firstly, five different extracts were prepared using sequential extraction, and screening of cell lines was performed using MTT assay.
    RESULTS: Lung cancer cells were selected as the most sensitive target, and dichloromethane extract (DE) was the most active extract. Annexin assay confirmed the mode of cell death as apoptosis. Sub-G1peak found in cell cycle analysis substantiated this finding. ROS generation and superoxide showed association with apoptotic death. The upregulation and overexpression of cleaved poly(ADP-ribose) polymerase-1(PARP-1) showed the failure of DNA repairing machinery contributing to apoptosis. LC-MS findings show the presence of cytotoxic actives cardamonin and alpinetin.
    CONCLUSIONS: In summary, this study shows the apoptosis-inducing potential of A. subulatum fruit extracts and confirms DNA damage as one of the causes of cell death. Further explorations using bio-fractionation and in-vivo studies are required to determine the most active constituents in A. subulatum.
    Keywords:  Amomum subulatum; Apoptosis; Lung cancer; MitoSox; ROS; Superoxide production
    DOI:  https://doi.org/10.1016/j.jep.2021.114953
  4. Anticancer Res. 2022 Jan;42(1): 547-554
    Effect of Alpha-tocopheryl Succinate on the Cytotoxicity of Anticancer Drugs Towards Leukemia Lymphocytes.
    Donika Ivanova, Zhivko Zhelev, Genoveva Zlateva, Dessislava Lazarova, Zvezdelina Yaneva, Radmila Panovska, Ichio Aoki, Rumiana Bakalova.
       BACKGROUND/AIM: This study analysed the effect of α-tocopheryl succinate (α-TS) on the redox-state of leukemia and normal lymphocytes, as well as their sensitization to fifteen anticancer drugs.
    MATERIALS AND METHODS: Cell viability was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by FITC-Annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products.
    RESULTS: Most combinations (α-TS plus anticancer drug) exerted additive or antagonistic effects on the proliferation and viability of leukemia lymphocytes. α-TS combined with barasertib, bortezomib or lonafarnib showed a strong synergistic cytotoxic effect, which was best expressed in the case of barasestib. It was accompanied by impressive induction of apoptosis and increased production of ROS, but insignificant changes in protein-carbonyl levels. α-TS plus barasertib did not alter the viability and did not induce oxidative stress and apoptosis in normal lymphocytes.
    CONCLUSION: α-TS could be a promising adjuvant in second-line anticancer therapy, particularly in acute lymphoblastic leukemia, to reduce the therapeutic doses of barasertib, bortezomib, and lonafarnib, increasing their effectiveness and minimizing their side effects.
    Keywords:  Chemotherapy; alpha-tocopheryl succinate; apoptosis; oxidative stress
    DOI:  https://doi.org/10.21873/anticanres.15512
  5. Eur J Pharmacol. 2021 Dec 22. pii: S0014-2999(21)00870-0. [Epub ahead of print]916 174714
    A bis-pyridinium fullerene derivative induces apoptosis through the generation of ROS in BCR-ABL-positive leukemia cells.
    Kazuya Sumi, Kenji Tago, Yosuke Nakazawa, Kyoko Takahashi, Tomoyuki Ohe, Tadahiko Mashino, Megumi Funakoshi-Tago.
      A fusion protein, Breakpoint cluster region-Abelson (BCR-ABL) is responsible for the development of chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL). Inhibitors against BCR-ABL are effective for the treatment of leukemia; however, a gatekeeper mutation (T315I) in BCR-ABL results in resistance to these inhibitors, which markedly impedes their efficacy. We herein demonstrated that a bis-pyridinium fullerene derivative (BPF) significantly induced apoptosis in human CML-derived K562 cells and ALL-derived SUP-B15 cells via the generation of reactive oxygen species (ROS). BPF reduced the expression of Bcr-Abl mRNA by inhibiting expression of c-Myc through ROS production. BPF also accelerated protein degradation of BCR-ABL through ROS production. Furthermore, BPF down-regulated the expression of not only BCR-ABL but also T315I-mutated BCR-ABL in ROS-dependent manner. As a result, BPF effectively induced apoptosis in transformed Ba/F3 cells expressing both BCR-ABL and T315I-mutated BCR-ABL. Collectively, these results indicate the potential of BPF as an effective leukemia drug that overcomes resistance to BCR-ABL inhibitors.
    Keywords:  Acute lymphocytic leukemia (ALL); BCR-ABL; Bis-pyridinium fullerene derivative (BPF); Chronic myeloid leukemia (CML); Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174714
  6. Front Oncol. 2021 ;11 770230
    Overexpression of Reactive Oxygen Species Modulator 1 Predicts Unfavorable Clinical Outcome in EGFR-Mutant Lung Adenocarcinomas Treated With Targeted Therapy.
    Won Gun Kwack, Ji-Youn Sung, Seung Hyeun Lee.
       Purpose: Reactive oxygen species modulator 1 (Romo1) is a novel protein that regulates the production of intracellular reactive oxygen species. Romo1 has been shown to be associated with poor survival in various clinical settings for the treatment of lung cancer. In this study, we evaluated whether tissue Romo1 expression was associated with clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma treated with tyrosine kinase inhibitors (TKIs).
    Method: Romo1 expression in tumor tissues was examined by immunohistochemistry and evaluated by histologic score. Univariate and multivariate analyses were performed to identify the clinicopathologic parameters, including Romo1 expression, which may be associated with progression-free survival (PFS), overall survival (OS), and incidence of secondary T790M mutation.
    Results: A total of 96 tumor specimens were analyzed. With the cut-off value of 200, 71 (74.0%) and 25 (26.0%) patients were classified into low and high Romo1 groups, respectively. The median PFS of the high Romo1 group was significantly shorter than that of the low Romo1 group (13.1 vs 19.9 months, p = 0.0165). The median OS of the high Romo1 group was also significantly shorter than that of the low Romo1 group (19.8 vs 37.0 months, p = 0.0006). Multivariate analyses showed that high Romo1 expression was independently associated with both poor PFS (hazard ratio [HR] = 2.48, 95% confidence interval [CI]: 1.35-4.56, p = 0.0034) and poor OS (HR = 3.17, 95% CI: 1.57-6.41, p = 0.0013). In addition, the rate of secondary T790M mutation after TKI failure was significantly lower in the high Romo1 group than the low Romo1 group (16.7% vs. 38.3%, p = 0.0369).
    Conclusions: Romo1 overexpression was associated with poor response to treatment and short survival in patients treated with EGFR-TKIs, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach. In addition, our data highlight that Romo1 could be a potential predictive and prognostic biomarker for this patient population.
    Keywords:  biomarker; epidermal growth factor receptor; reactive oxygen species modulator 1; survival; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2021.770230
  7. Pathol Int. 2021 Dec 29.
    Asbestos-induced mesothelial injury and carcinogenesis: Involvement of iron and reactive oxygen species.
    Yasumasa Okazaki.
      Asbestos fibers have been used as an industrial and construction material worldwide due to their high durability and low production cost. Commercial usage of asbestos is currently prohibited in Japan; however, the risk of asbestos-induced malignant mesothelioma (MM) remains. According to epidemiological data, the onset of MM is estimated to occur after a latent period of 30-40 years from initial exposure to asbestos fibers; thus, the continuous increase in MM is a concern. To explore the molecular mechanisms of MM using animal models, iron saccharate with iron chelator-induced sarcomatoid mesothelioma (SM) revealed hallmarks of homozygous deletion of Cdkn2a/2b by aCGH and microRNA-199/214 by expression microarray. Oral treatment of iron chelation by deferasirox decreased the rate of high-grade SM. Moreover, phlebotomy delayed MM development in crocidolite-induced MM in rats. In Divalent metal transporter 1 (Dmt1) transgenic mice, MM development was delayed because of low reactive oxygen species (ROS) production. These results indicate the importance of iron and ROS in mesothelial carcinogenesis. The aims of this review focus on the pathogenesis of elongated mineral particles (EMPs), including asbestos fibers and multiwalled carbon nanotubes (MWCNTs) that share similar rod-like shapes in addition to the molecular mechanisms of MM development.
    Keywords:  asbestos; carbon nanotubes; iron; malignant mesothelioma; oxidative stress
    DOI:  https://doi.org/10.1111/pin.13196
  8. Pathol Res Pract. 2021 Dec 17. pii: S0344-0338(21)00403-9. [Epub ahead of print]230 153742
    Development of cervical intraepithelial lesions and cervical cancer is not influenced by SOD2 RS4880 polymorhism.
    Rafaela Roberta de Jaime Curti, Eliza Pizarro Castilha, Ana Luiza Labbate Bonaldo, Nádia Calvo Martins Okuyama, Kleber Paiva Trugilo, Roberta Losi Guembarovski, José d'Oliveira Couto-Filho, Maria Angelica Ehara Watanabe, Karen Brajão de Oliveira.
      Some of the more than 200 known HPV types are essential for cervical cancer development, the third type of cancer most incident in the female population. However, for the malignant transformation occur, some cofactors are needed, as the reactive oxygen species (ROS), which can be neutralized by the antioxidant system. The SOD2 enzyme, encoded by the same name gene, is found in mitochondria and is part of the first line of defense against oxidative stress damage. Genetic polymorphisms can act by altering the efficiency of the enzyme, among which the most studied is the rs4880. Thus, the purpose of the present study was to evaluate the association of this polymorphism with HPV infection and the development of low and high grade squamous intraepithelial lesions (LSIL and HSIL) and cervical cancer, in 407 women attended by the public health system in Brazil. HPV detection in cervical secretion samples was carried out by polymerase chain reaction (PCR) and blood samples were used for polymorphism genotyping through PCR followed by restriction fragment length polymorphism (RFLP). PCR and restriction products were subjected to 10% polyacrylamide gel electrophoresis. HPV negative group (control) included 158 women and the HPV positive group (case) 249 women. The infected group was divided into No Lesion (n = 90), LSIL (n = 20), HSIL (n = 67) and cervical cancer (n = 72). The data found on socio-epidemiological characteristics and habits corroborated with data found in the literature. The distribution of genotypes in the control group was 51.9% women TC, 29.8% TT and 18.3% CC. In the case group, the distribution was 55.0% women TC, 26.1% TT and 18.9% CC. This is the first study evaluating the influence of SOD2 rs4880 polymorphism on HPV infection, the development of cervical intraepithelial lesions and cervical cancer in a Brazilian population, although additional studies are needed to corroborate the results.
    Keywords:  Cervical intraepithelial lesions; Human papillomavirus; MnSOD; Molecular diagnosis; Oxidative stress; Val16Ala
    DOI:  https://doi.org/10.1016/j.prp.2021.153742
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