Irinotecan Activates p53 With Its Active Metabolite, Resulting in Human Hepatocellular Carcinoma Apoptosis

Takeba, Yuko; Kumai, Toshio; Matsumoto, Naoki; Nakaya, Shinji; Yoshimitsu, Tetsuo; Yanagida, Yohei; Kobayashi, Shinichi

doi:10.1254/jphs.fp0070442

Cited by 45 publications

(33 citation statements)

References 39 publications

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“…The DNA laddering characteristic of apoptosis (data not shown) in MCF-7 cells occurred in a dose-and timedependent manner, reconfirming that CPA with or without RES induced apoptosis. In response to DNA damage to the cell, the posttranslational modification of tumor suppressor protein p53 is known to inhibit cell growth and apoptosis (32). The p53 gene is also known to regulate the G1 checkpoint, which can either induce cell cycle arrest (increased expression of p21 Waf1 /Cip1) or initiate apoptosis (decreased expression of p21 Waf1 /Cip1).…”

Section: Discussionmentioning

confidence: 99%

Caspase Mediated Enhanced Apoptotic Action of Cyclophosphamide- and Resveratrol-Treated MCF-7 Cells

et al. 2009

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Abstract. Cyclophosphamide (CPA) is a widely used chemotherapeutic drug for neoplasias. It is a DNA and protein alkylating agent having a broad spectrum of activity against a variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the highdose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining resveratrol (RES) with CPA and aims to increase the understanding of the mechanism of cell killing. Interestingly, we found that RES significantly enhances the caspase-mediated cytotoxic activity of CPA on MCF-7 cells in vitro. RES at 50 μM decreases the IC 50 value of CPA from 10 to 5 mM. FACS data reveals CPA or RES alone mediated G0/ G1 and S phase arrest, while the combination of these drugs released both the arrests and results in an increase in the sub G0/G1 peak. Additional analyses indicated the significant up-regulation (P = 0.001) of tumor suppressor p53 and p53-regulated pro-apoptotic Bax and Fas in MCF-7 cells following CPA treatment in combination with RES, which may contribute to the enhancement of the antitumor effect of CPA. Furthermore, downregulation of anti-apoptotic Bcl-2 (P = 0.001) was observed in MCF-7 cells treated with CPA with or without RES when compared to untreated MCF-7. These results suggest the possibility of a new combination chemotherapeutic regimen leading to improvements in the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Caspase Mediated Enhanced Apoptotic Action of Cyclophosphamide- and Resveratrol-Treated MCF-7 Cells

et al. 2009

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“…The nuclear and cytoplasm proteins in primary hepatocytes were prepared using a commercial kit (NE-PER, nuclear and cytoplasmic extraction kit; Pierce Biotechnology, Rockford, IL, USA) (19). The protein concentration was determined with a Bio-Rad protein assay kit (Bio-Rad, Hercules, CA, USA).…”

Section: Western Blot Analysismentioning

confidence: 99%

Comparative Study of Culture Conditions for Maintaining CYP3A4 and ATP-Binding Cassette Transporters Activity in Primary Cultured Human Hepatocytes

et al. 2011

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Abstract. The aim of this study was to determine suitable culture conditions for maintaining the activity of cytochrome p450 (CYP) 3A4 and drug transporters in primary cultured human hepatocytes. Human hepatocytes were isolated using the two-step collagenase perfusion technique and were cultured with four different media, serum-free William's E medium (serum-free WEM), WEM containing fetal calf serum (FCS-WEM), WEM with human serum (HS-WEM), and Lanford's medium. The albumin levels were maintained for 7 days in hepatocytes. Although CYP3A4 mRNA levels gradually decreased from 3 days, CYP3A4 and hepatocyte nuclear factor-4α alpha protein levels and activities were maintained for 7 days in hepatocytes cultured with serum-free WEM and Lanford's but not in those with FCS-WEM and HS-WEM. Furthermore, CYP3A4 protein levels were significantly increased by the addition of rifampicin and dexamethasone to the culture media, indicating that the induction potential was maintained. The protein levels of P-glycoprotein, multi-drug-resistance-2, and breast cancer-resistance protein were maintained for 7 days in all media. Serum-free WEM and Lanford's also maintained protein levels of CYP2C19, CYP2D6, and organic anion transporter polypeptide in the hepatocytes. Serum-free WEM and Lanford's may be appropriate culture media for maintaining CYP3A4 and drug transporter protein levels in primary cultured hepatocytes.

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“…Thus, irinotecan might prolong survival time of HCC patients and might be a potential drug for their treatment [10,12,13]. Some studies have already evaluated TACE using a combination of mitomycin and irinotecan treatment of HCC.…”

Section: Discussionmentioning

confidence: 99%

Transarterial Chemoembolization (TACE) Using Mitomycin with or without Irinotecan for Hepatocellular Carcinoma in European Patients

Gruber‐Rouh¹,

Kamal²,

Eichler³

et al. 2018

Oncol Res Treat

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Background: We evaluated survival data and local tumor control in 2 groups of patients with hepatocellular carcinoma (HCC) treated with different chemotherapeutic agents for transarterial chemoembolization (TACE). Methods: 28 patients (median age 63 years) with HCC were repeatedly treated with chemoembolization at 4-week intervals. 20 patients had Barcelona Clinic Liver Cancer (BCLC) stage B, while 8 patients obtained chemoembolization for bridging purposes (BCLC stage A). In total, 98 chemoembolizations were performed (median 3.0 treatments/patient). The administered chemotherapeutic agent comprised either mitomycin only (n = 14; 50%) or mitomycin in combination with irinotecan (n = 14; 50%). Lipiodol plus degradable starch microspheres was used for all embolizations. Local tumor response was assessed by magnetic resonance imaging using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Progression-free survival (PFS) was evaluated. Results: In the mitomycin-irinotecan group, complete response (CR) was observed in 21.4%, partial response (PR) in 42.9%, stable disease (SD) in 28.6%, and progressive disease (PD) in 7.1%. In the mitomycin group, PR was observed in 57.2% of patients, SD in 21.4%, and PD in 21.4% (p = 0.043). The PFS of patients after chemoembolization with mitomycin was 4 months compared to the significantly longer PFS of 12 months in the mitomycin-irinotecan group (p = 0.003). Conclusion: Chemoembolization of HCC with mitomycin and irinotecan is the preferred treatment option for achieving local control and better PFS.

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Irinotecan Activates p53 With Its Active Metabolite, Resulting in Human Hepatocellular Carcinoma Apoptosis

Cited by 45 publications

References 39 publications

Caspase Mediated Enhanced Apoptotic Action of Cyclophosphamide- and Resveratrol-Treated MCF-7 Cells

Caspase Mediated Enhanced Apoptotic Action of Cyclophosphamide- and Resveratrol-Treated MCF-7 Cells

Comparative Study of Culture Conditions for Maintaining CYP3A4 and ATP-Binding Cassette Transporters Activity in Primary Cultured Human Hepatocytes

Transarterial Chemoembolization (TACE) Using Mitomycin with or without Irinotecan for Hepatocellular Carcinoma in European Patients

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