Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism

Jiang, Shun Yuan; Shyu, Rong-Yaun; Yeh, Ming‐Yang; Jordan, V. Craig

doi:10.1097/00042737-199604000-00027

Cited by 6 publications

(11 citation statements)

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“…60 Nevertheless, tamoxifen has been shown to inhibit hepatocyte proliferation after partial hepatectomy and to inhibit HCC growth through an estrogen receptor-independent mechanisim. 61 Tamoxifen, an antiestrogen, has been extensively studied in patients with unresectable HCC. Initially, three studies demonstrated a survival benefit for tamoxifen in patients with advanced HCC.…”

Section: Hormonal Therapymentioning

confidence: 99%

Systemic therapy of hepatocellular carcinoma: Are we making progress?

Roxburgh

Evans

2008

Adv Therapy

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Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer deaths. Surgical resection, with or without transplantation, can result in long-term survival. However, surgery can only be performed in about 15% of patients with HCC and the 5-year survival rate is only approximately 33%-50% after potentially curative resection. Percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are invasive techniques that have shown efficacy in reducing tumor bulk. Similarly, systemic chemotherapy may induce tumor responses, but a survival benefit has not been clearly demonstrated. In addition, the lack of efficacy of antiandrogens, tamoxifen, and single-agent interferon has now been confirmed.Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory activity. In a large, multicenter, randomized, phase 3 trial there was a significant improvement in both time to disease progression and overall survival with sorafenib compared with placebo. Sorafenib is the first agent to demonstrate a consistent improvement in overall survival for patients with advanced HCC. Further studies are required to determine the role of other molecular-targeted therapies, either alone or in combination with sorafenib in patients with advanced HCC. Further studies are also required to determine the role of sorafenib in combination with locoregional therapies (eg, transarterial chemoembolization), and the role of sorafenib as adjuvant therapy following surgery.

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Section: Hormonal Therapymentioning

confidence: 99%

Systemic therapy of hepatocellular carcinoma: Are we making progress?

Roxburgh

Evans

2008

Adv Therapy

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“…[9][10][11][12][13][14] However, TMX at higher dosages (6-8 times that used for ER-positive breast carcinoma) is known to have therapeutic actions independent of ER status, 15 and such ER-independent mechanisms for TMX have been shown in HCC. 16,17 Thus, high-dose TMX would theoretically have therapeutic actions on both ER-positive and -negative HCC. 18,19 This multicenter trial was designed to test this hypothesis and assess the possible dose-response relation of TMX with respect to survival and quality of life (QoL) in patients with inoperable HCC.…”

mentioning

confidence: 99%

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial

et al. 2002

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In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens (P ‫؍‬ .011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed. H epatocellular carcinoma (HCC) is an important malignancy worldwide. In many parts of the Asia-Pacific region, the age-standardized mortality is in excess of 20 per 100,000. Surgery currently offers the only chance of prolonged survival, but only 10% to 15% of HCCs are operable at diagnosis. 1,2 There is currently no proven treatment modality that prolongs survival in patients with inoperable HCC. 3 Estrogen receptor (ER)-positive HCC responds to treatment with tamoxifen (TMX), 4 but more than 50% of HCCs are ER negative, including HCCs found in southeast Asia. 5-8 TMX at dosages relevant for ER-positive breast carcinoma (20-60 mg/d) was nevertheless used in a number of phase 3 trials in which the ER status of HCC was not determined. The results of these trials have been conflicting and inconclusive. [9][10][11][12][13][14] However, TMX at higher dosages (6-8 times that used for ER-positive breast carcinoma) is known to have therapeutic actions independent of ER status, 15 and such ER-independent mechanisms for TMX have been shown in HCC. 16,17 Thus, high-dose TMX would theoretically have therapeutic actions on both ER-positive and -negative HCC. 18,19 This multicenter trial was designed to test this hypothesis and

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“…For this purpose, the human hepatoblastoma cell line HepG2 provides an excellent in vitro system. In HepG2 cells, ER-a is not detectable [20] or expressed at low levels which are insufficient for ligands to affect transactivation of ER-regulated genes [31]. On the other hand, HepG2 cells have been shown to retain many of the different characteristics of normal hepatocytes, although the cell line performs uraegenesis, glucuronidation, sulfation, and oxidative metabolism at least by a factor 10 lower than primary rat hepatocytes, whereas the rate of albumin synthesis is higher [19].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it has been shown to bring benefits to patients with other malignant disorders, such as hepatocellular carcinoma (HCC) in the advanced inoperable stage [12]. Cell culture experiments on the human hepatoblastoma cell lines Hep3B and HepG2 have shown that tamoxifen at concentrations in the nanomolar range induces growth-inhibition and/or apoptotic cell death via an estrogen-receptor-a (ER-a)-independent mechanism [5,20]. This is in line with the low ERa-expression in most HCC tissues.…”

Section: Introductionmentioning

confidence: 99%

“…In the breast cancer cell lines MCF7, down-regulation of telomerase activity during tamoxifen treatment is at least in part due to a suppression of hTERT mRNA expression [2] mediated through binding of the tamoxifen-ERa-complex to an estrogen-responsive element in the hTERT-5'regulatory region [39]. Since in HepG2 cells estrogen-receptors are not detectable [20] or are expressed at low levels which are insufficient for ligands to affect transactivation of ER-regulated genes [31], other mechanisms through which tamoxifen could alter telomerase activity have to be considered. We show here that in HepG2 cells tamoxifen may reduce telomerase activity on the posttranslational level via suppression of protein kinase C (PKC) activity.…”

Section: Introductionmentioning

confidence: 99%

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