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Updated: May 6, 2026
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Targeting phosphodiesterase 3B enhances cisplatin sensitivity in human cancer cells
Katsuhiro Uzawa1, Atsushi Kasamatsu, Takao Baba
1Department of Clinical Molecular Biology, Graduate School of Medicine, Chiba University Chiba, 260-8670, Japan ; Department of Dentistry-Oral and Maxillofacial Surgery, Chiba University Hospital Chiba, 260-8677, Japan.
Abstract:
We previously reported that human squamous cell carcinoma (SCC) cell lines refractory to cis-diaminedichloro-platinum II (cisplatin [CDDP]) had significant upregulation of the phosphodiesterase 3B gene (PDE3B), suggesting that inhibiting PDE3B suppresses CDDP resistance. shRNA-mediated PDE3B depletion in CDDP-resistant cells derived from SCC cells and Hela cells and induced CDDP sensitivity and inhibited tumor growth with elevated cyclic GMP induction resulting in upregulation of the multidrug-resistant molecule, but this did not occur in the 5-fluorouracil-resistant hepatocellular carcinoma cell lines. Furthermore, the antitumor growth effect of the combination of a PDE3B inhibitor (cilostazol) and CDDP in vivo was also greater than with either cilostazol or CDDP alone, with a significant increase in the number of apoptotic and cell growth-suppressive cancer cells in CDDP-resistance cell lines. Our results provided novel information on which to base further mechanistic studies of CDDP sensitization by inhibiting PDE3B in human cancer cells and for developing strategies to improve outcomes with concurrent chemotherapy.
Insights
Inhibiting phosphodiesterase 3B (PDE3B) resensitizes cisplatin-resistant cancer cells to chemotherapy. Combining a PDE3B inhibitor with cisplatin enhances antitumor effects and cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cisplatin (CDDP) resistance is a major challenge in squamous cell carcinoma (SCC) treatment.
- Upregulation of phosphodiesterase 3B (PDE3B) was observed in CDDP-refractory SCC cell lines.
Purpose of the Study:
- To investigate the role of PDE3B in CDDP resistance.
- To evaluate the therapeutic potential of inhibiting PDE3B in combination with CDDP.
Main Methods:
- shRNA-mediated depletion of PDE3B in CDDP-resistant SCC and Hela cells.
- Assessment of CDDP sensitivity, tumor growth, and cyclic GMP levels.
- In vivo studies combining a PDE3B inhibitor (cilostazol) with CDDP.
Main Results:
- PDE3B depletion restored CDDP sensitivity and inhibited tumor growth in SCC and Hela cells.
- Elevated cyclic GMP was observed, but multidrug-resistant molecule upregulation did not occur.
- Combination therapy with cilostazol and CDDP demonstrated superior antitumor efficacy compared to monotherapy.
- Significant increases in apoptosis and suppressed cell growth were noted in CDDP-resistant cell lines.
Conclusions:
- Inhibiting PDE3B is a promising strategy to overcome CDDP resistance in human cancer cells.
- Combination of PDE3B inhibitors with CDDP may improve chemotherapy outcomes.
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