Targeting phosphodiesterase 3<scp>B</scp> enhances cisplatin sensitivity in human cancer cells

Uzawa, Katsuhiro; Kasamatsu, Atsushi; Baba, Takao; Usukura, Katsuya; Saito, Yasuhiro; Sakuma, Kei; Iyoda, Manabu; Sakamoto, Yosuke; Ogawara, Katsunori; Shiiba, Masashi; Tanzawa, Hideki

doi:10.1002/cam4.56

Cited by 21 publications

(17 citation statements)

References 37 publications

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“…Two cisplatin‐resistant oral squamous cell carcinoma cell lines, Sa‐3R and H‐1R cells, exhibited increased expression of PDE3B compared with parental cell lines (Yamano et al , ), and, as assessed by PDE3B immunohistochemical staining, PDE3B expression levels were significantly higher in the tumors unresponsive to cisplatin than in responsive tumors (Yamano et al , ). Furthermore, the antitumor growth effect of the combination of a PDE3‐specific inhibitor (cilostazol) and cisplatin was also greater than with either cilostazol or cisplatin, with a significant increase in the number of apoptotic and cell growth‐suppressive cancer cells in cisplatin‐resistant Sa‐R cells (Uzawa et al , ). In human neoplastic submandibular gland intercalated duct HSG cell lines, PDE3A and PDE3B mRNAs were expressed and a PDE3‐specific inhibitor (cilostamide) inhibited proliferation of these cells (Murata et al , ).…”

Section: Pdes As Possible Targets In Oral Cancermentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

et al. 2014

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By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.

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Section: Pdes As Possible Targets In Oral Cancermentioning

confidence: 99%

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

et al. 2014

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“…To further investigate the mechanism by which reduction of PDE3B alters CDDP resistance, Sa3‐R and HeLa‐R cells were exposed to cilostazol. Both CDDP‐resistant cells had enhanced CDDP sensitivity in the presence of cilostazol with elevated cAMP/cGMP activation [].…”

Section: Overcoming Chemoresistance In Cancer Cellsmentioning

confidence: 99%

“…The tumor tissues from the control, cilostazol alone, CDDP alone, and combination groups were fixed in 10% formalin, and paraffin sections (4 μm) were prepared for hematoxylin and eosin staining and immunohistochemistry of proliferating cell nuclear antigen (PCNA), Ki67, and cleaved caspase3 assay. Original magnification 400× [].…”

Section: Overcoming Chemoresistance In Cancer Cellsmentioning

confidence: 99%

“…Data represent the mean ± SEM. The asterisks indicate significant differences from the controls ( * P < 0.05, ** P < 0.01, respectively, Mann–Whitney U test) [].…”

Section: Overcoming Chemoresistance In Cancer Cellsmentioning

confidence: 99%

“…Of these, two methods, which we previously reported in the journals of Oncogene (2011) [] and Cancer Med. (2013) [], are introduced in this article.…”

Section: Introductionmentioning

confidence: 99%

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Targeting gene therapies enhance sensitivity to chemo‐ and radiotherapy of human oral squamous cell carcinoma

Tanzawa

Uzawa

Kasamatsu

et al. 2015

Oral Science International

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We have developed two methods to enhance the sensitivity of chemo‐ and/or radioresistant oral squamous carcinoma cells (OSCC). One is a method to inhibit a chemoresistant gene and to enhance sensitivity to chemotherapy. Most of the cases with resistance to cis‐diaminedichloro‐platinum II (cisplatin, CDDP) shows significant upregulated expression of phosphodiesterase 3B (PDE3B) and inhibition of PDE3B by cilostazol, which is clinically used as an antiplatelet drug for peripheral vascular disease, suppressing multidrug resistance‐associated proteins (MRPs), a subfamily of adenosine triphosphate (ATP)‐binding cassette (ABC) transporters, thus resulting in an increased amount of anticancer drugs such as CDDP. The combination usage of cilostazol and CDDP in vitro and in vivo indicated greater growth suppression of chemoresistant OSCC than that of either cilostazol alone or CDDP alone. The other method involves using a drug that inhibits radioresistance and enhances sensitivity to radiotherapy. Human oral squamous cancer cell lines exhibiting radioresistance show significant upregulated expression of the fibroblast growth factor receptor 3 (FGFR3). In vitro and in vivo, PD173074, a chemical agent inhibiting FGFR3, showed significant enhanced effect of radiation therapy on radioresistant cancer cells. These results provided novel information on which to base further mechanistic study on developing strategies to improve outcomes with concurrent chemo‐ and/or radiotherapy.

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DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas

Tsuda

Tian

Fujimoto

et al. 2022

J Cancer Res Clin Oncol

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Purpose This study was performed to identify the DNA methylation profiles underlying the clinicopathological diversity of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). Methods Genome-wide DNA methylation analysis of 88 liver tissue samples was performed using the Infinium assay. Results Principal component analysis revealed that distinct DNA methylation profiles differing from such profiles in normal control liver tissue had already been established in non-cancerous liver tissue showing NASH, which is considered to be a precancerous condition. Hierarchical clustering separated 26 NASH-related HCCs into Cluster I (n = 8) and Cluster II (n = 18). Such epigenetic clustering was significantly correlated with histopathological diversity, i.e. poorer tumor differentiation, tumor steatosis and development of a scirrhous HCC component. Significant differences in DNA methylation levels between the two clusters were accumulated in molecular pathways participating in cell adhesion and cytoskeletal remodeling, as well as cell proliferation and apoptosis. Among tumor-related genes characterizing Clusters I and II, differences in the levels of DNA methylation and mRNA expression for the SPHK1, INHBA, LTB and PDE3B genes were correlated with poorer tumor differentiation. 5-Aza-2′-deoxycytidine treatment of HCC cells revealed epigenetic regulation of the SPHK1 and LTB genes. Knockdown experiments showed that SPHK1 promotes cell proliferation, represses apoptosis and enhances migration, whereas LTB enhances migration of HCC cells. DNA hypomethylation resulting in increased expression of SPHK1 and LTB in poorly differentiated HCCs may underlie the aggressive phenotype of such HCCs. Conclusion These data indicate that DNA methylation profiles may determine the clinicopathological heterogeneity of NASH-related HCCs via alterations of tumor-related gene expression.

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Targeting phosphodiesterase 3B enhances cisplatin sensitivity in human cancer cells

Cited by 21 publications

References 37 publications

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

Targeting gene therapies enhance sensitivity to chemo‐ and radiotherapy of human oral squamous cell carcinoma

DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas

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