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15 pages, 3779 KiB

Open AccessArticle

Radiosensitization to γ-Ray by Functional Inhibition of APOBEC3G

by Ying Tong, Sota Kikuhara, Takae Onodera, Lichao Chen, Aung Bhone Myat, Shoji Imamichi, Yuka Sasaki, Yasufumi Murakami, Tadashige Nozaki, Hiroaki Fujimori and Mitsuko Masutani

Int. J. Mol. Sci. 2022, 23(9), 5069; https://doi.org/10.3390/ijms23095069 - 03 May 2022

Cited by 1 | Viewed by 1778

Abstract

The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 [...] Read more.

The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 using an shRNA library and identified apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G: A3G) as a candidate target. APOBEC3G is an innate restriction factor that inhibits HIV-1 infection as a cytidine deaminase. APOBEC3G knockdown with siRNA showed an increased radiosensitivity in several cancer cell lines, including pancreatic cancer MIAPaCa2 cells and lung cancer A549 cells. Cell cycle analysis revealed that APOBEC3G knockdown increased S-phase arrest in MIAPaCa2 and G2/M arrest in A549 cells after γ-irradiation. DNA double-strand break marker γH2AX level was increased in APOBEC3G-knocked-down MIAPaCa2 cells after γ-irradiation. Using a xenograft model of A549 in mice, enhanced radiosensitivity by a combination of X-ray irradiation and APOBEC3G knockdown was observed. These results suggest that the functional inhibition of APOBEC3G sensitizes cancer cells to radiation by attenuating the activation of the DNA repair pathway, suggesting that APOBEC3G could be useful as a target for the radiosensitization of cancer therapy. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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10 pages, 1697 KiB

Open AccessArticle

Inhibition of Poly (ADP-Ribose) Glycohydrolase Accelerates Osteoblast Differentiation in Preosteoblastic MC3T3-E1 Cells

by Yuka Sasaki, Ryusuke Nakatsuka, Takuma Inouchi, Mitsuko Masutani and Tadashige Nozaki

Int. J. Mol. Sci. 2022, 23(9), 5041; https://doi.org/10.3390/ijms23095041 - 02 May 2022

Cited by 4 | Viewed by 2218

Abstract

Poly ADP-ribosylation (PARylation) is a post-translational modification catalyzed by poly (ADP-ribose) polymerase (PARP) family proteins such as PARP1. Although PARylation regulates important biological phenomena such as DNA repair, chromatin regulation, and cell death, little is known about the relationship between osteoblast differentiation and [...] Read more.

Poly ADP-ribosylation (PARylation) is a post-translational modification catalyzed by poly (ADP-ribose) polymerase (PARP) family proteins such as PARP1. Although PARylation regulates important biological phenomena such as DNA repair, chromatin regulation, and cell death, little is known about the relationship between osteoblast differentiation and the PARylation cycle involving PARP1 and the poly (ADP-ribose)-degrading enzyme poly (ADP-ribose) glycohydrolase (PARG). Here, we examined the effects of PARP inhibitor olaparib, an approved anti-cancer agent, and PARG inhibitor PDD00017273 on osteoblast differentiation. Olaparib decreased alkaline phosphatase (ALP) activity and suppressed mineralized nodule formation evaluated by Alizarin Red S staining in preosteoblastic MC3T3-E1 cells, while PDD00017273 promoted ALP activity and mineralization. Furthermore, PDD00017273 up-regulated the mRNA expression levels of osteocalcin and bone sialoprotein, as osteoblast differentiation markers, and osterix as transcription inducers for osteoblast differentiation, whereas olaparib down-regulated the expression of these genes. These findings suggest that PARG inhibition by PDD00017273 accelerates osteoblast differentiation in MC3T3-E1 cells. Thus, PARG inhibitor administration could provide therapeutic benefits for metabolic bone diseases such as osteoporosis. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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13 pages, 3690 KiB

Open AccessArticle

PARP Inhibitor Decreases Akt Phosphorylation and Induces Centrosome Amplification and Chromosomal Aneuploidy in CHO-K1 Cells

by Masakazu Tanaka, Masatoshi Mushiake, Jun Takahashi, Yuka Sasaki, Sachiko Yamashita, Chieri Ida, Mitsuko Masutani and Masanao Miwa

Int. J. Mol. Sci. 2022, 23(7), 3484; https://doi.org/10.3390/ijms23073484 - 23 Mar 2022

Cited by 2 | Viewed by 1540

Abstract

Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and [...] Read more.

Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and chromosomal aneuploidy. Thus, the processes of carcinogenesis and killing cancer cells might have some mechanisms in common. Previously, we found that the inhibitors of polyADP-ribosylation, a post-translational modification of proteins, caused centrosome amplification. However, the mechanism of action of the inhibitors of polyADP-ribosylation is not fully understood. In this study, we found that an inhibitor of polyADP-ribosylation, 3-aminobenzamide, caused centrosome amplification, as well as aneuploidy of chromosomes in CHO-K1 cells. Moreover, inhibitors of polyADP-ribosylation inhibited AKT phosphorylation, and inhibitors of AKT phosphorylation inhibited polyADP-ribosylation, suggesting the involvement of polyADP-ribosylation in the PI3K/Akt/mTOR signaling pathway for controlling cell proliferation. Our data suggest a possibility for developing drugs that induce centrosome amplification and aneuploidy for therapeutic applications to clinical cancer. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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19 pages, 11802 KiB

Open AccessArticle

A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling

by Sei-ichi Tanuma, Takahiro Oyama, Miwa Okazawa, Hiroaki Yamazaki, Koichi Takao, Yoshiaki Sugita, Shigeru Amano, Takehiko Abe and Hiroshi Sakagami

Int. J. Mol. Sci. 2022, 23(7), 3426; https://doi.org/10.3390/ijms23073426 - 22 Mar 2022

Cited by 7 | Viewed by 2276

Abstract

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility [...] Read more.

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)–receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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19 pages, 7078 KiB

Open AccessArticle

Possible Action of Olaparib for Preventing Invasion of Oral Squamous Cell Carcinoma In Vitro and In Vivo

by Nanami Nakamura, Hisako Fujihara, Koji Kawaguchi, Hiroyuki Yamada, Ryoko Nakayama, Masaaki Yasukawa, Yuta Kishi, Yoshiki Hamada and Mitsuko Masutani

Int. J. Mol. Sci. 2022, 23(5), 2527; https://doi.org/10.3390/ijms23052527 - 25 Feb 2022

Cited by 3 | Viewed by 2582

Abstract

Despite recent advances in treatment, the prognosis of oral cancer remains poor, and prevention of recurrence and metastasis is critical. Olaparib is a PARP1 inhibitor that blocks polyADP-ribosylation, which is involved in the epithelial–mesenchymal transition (EMT) characteristic of tumor recurrence. We explored the [...] Read more.

Despite recent advances in treatment, the prognosis of oral cancer remains poor, and prevention of recurrence and metastasis is critical. Olaparib is a PARP1 inhibitor that blocks polyADP-ribosylation, which is involved in the epithelial–mesenchymal transition (EMT) characteristic of tumor recurrence. We explored the potential of olaparib in inhibiting cancer invasion in oral carcinoma using three oral cancer cell lines, HSC-2, Ca9-22, and SAS. Olaparib treatment markedly reduced their proliferation, migration, invasion, and adhesion. Furthermore, qRT-PCR revealed that olaparib inhibited the mRNA expression of markers associated with tumorigenesis and EMT, notably Ki67, Vimentin, β-catenin, MMP2, MMP9, p53, and integrin α2 and β1, while E-Cadherin was upregulated. In vivo analysis of tumor xenografts generated by injection of HSC-2 cells into the masseter muscles of mice demonstrated significant inhibition of tumorigenesis and bone invasion by olaparib compared with the control. This was associated with reduced expression of proteins involved in osteoclastogenesis, RANK and RANKL. Moreover, SNAIL and PARP1 were downregulated, while E-cadherin was increased, indicating the effect of olaparib on proteins associated with EMT in this model. Taken together, these findings confirm the effects of olaparib on EMT and bone invasion in oral carcinoma and suggest a new therapeutic strategy for this disease. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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13 pages, 2892 KiB

Open AccessArticle

Curcumin as an Epigenetic Therapeutic Agent in Myelodysplastic Syndromes (MDS)

by Xiaoqing Xie, Daria Frank, Pradeep Kumar Patnana, Judith Schütte, Yahya Al-Matary, Longlong Liu, Lanying Wei, Martin Dugas, Julian Varghese, Subbaiah Chary Nimmagadda and Cyrus Khandanpour

Int. J. Mol. Sci. 2022, 23(1), 411; https://doi.org/10.3390/ijms23010411 - 30 Dec 2021

Cited by 4 | Viewed by 2123

Abstract

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 [...] Read more.

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or –KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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14 pages, 2568 KiB

Open AccessArticle

Arylamine Analogs of Methylene Blue: Substituent Effect on Aggregation Behavior and DNA Binding

by Alena Khadieva, Olga Mostovaya, Pavel Padnya, Valeriy Kalinin, Denis Grishaev, Dmitrii Tumakov and Ivan Stoikov

Int. J. Mol. Sci. 2021, 22(11), 5847; https://doi.org/10.3390/ijms22115847 - 29 May 2021

Cited by 11 | Viewed by 2875

Abstract

The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, [...] Read more.

The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, i.e., 3,7-bis(4-aminophenylamino)phenothiazin-5-ium chloride dihydrochloride (PTZ1) and 3,7-bis(4-sulfophenylamino)phenothiazin-5-ium chloride (PTZ2), are synthesized for the first time and characterized by NMR, IR spectroscopy, HRMS and elemental analysis. The interaction of the obtained compounds PTZ1 and PTZ2 with salmon sperm DNA is investigated. It is shown by UV-Vis spectroscopy and DFT calculations that substituents in arylamine fragments play a crucial role in dimer formation and interaction with DNA. In the case of PTZ1, two amine groups promote H-aggregate formation and DNA interactions through groove binding and intercalation. In the case of PTZ2, sulfanilic acid fragments prevent any dimer formation and DNA binding due to electrostatic repulsion. DNA interaction mechanisms are studied and confirmed by UV-vis and fluorescence spectroscopy in comparison with Methylene Blue. The obtained results open significant opportunities for the development of new drugs and photodynamic agents. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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Review

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24 pages, 3770 KiB

Open AccessReview

Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy

by Yoshihisa Matsumoto

Int. J. Mol. Sci. 2022, 23(8), 4264; https://doi.org/10.3390/ijms23084264 - 12 Apr 2022

Cited by 11 | Viewed by 3383

Abstract

DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts [...] Read more.

DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy. Full article

(This article belongs to the Special Issue Therapeutic Drugs Targeting DNA)

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