Tamoxifen

IC50: 5.5–10 μM

Transforming growth factor-β (TGF-β) is a growth factor which is capable of inhibiting prostate cell growth in vitro, and has apparent prostate cell growth regulatory roles in vivo. A second element of potential importance in regulating the growth of prostate cancer cells is the serine/threonine kinase, protein kinase C (PKC). PKC is a signaling enzyme of known importance in regulating the growth and/or differentiation of a variety of cell types; inhibition of its kinase activity is associated with loss of regulatory function. Tamoxifen is a drug known to have TGF-β modulatory and PKC inhibitory effects.

In vitro: IC50s for growth inhibition ranged from 5.5–10 μM, and were not affected by estrogen. Tamoxifen-mediated growth inhibition was not associated with induction of TGF-β. However, tamoxifen treatment was associated with inhibition of PKC, which was followed by induction of p21waf1/cip1, Rb dephosphorylation, and G1/S phase cell cycle arrest [1].

In vivo: The tumor cell kinetics of MCF-7 human breast carcinoma xenografts grown in nude mice can be significantly altered by hormonal manipu lation. Tamoxifen treatment or E2 deprivation resulted in an approximate doubling of the Tpol and an approximately 40% reduction in labeling index as compared to E2-stimulated tumors. An increase in cell loss rate was calculated for both tamoxifen treatment and E2 deprivation [2].

Clinical trial: Tamoxifen reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy, and it provides effective palliation for metastatic breast cancer. Its use is therefore indicated for both premenopausal and postmenopausal women having estrogen-receptor–positive invasive breast cancer [3].

References:
[1] Rohlff C, Blagosklonny MV, Kyle E, Kesari A, Kim IY, Zelner DJ, Hakim F, Trepel J, Bergan RC.  Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1). Prostate. 1998 Sep 15;37(1):51-9.
[2] Jann N.  Sarkaria, David F. C. Gibson, V. Craig Jordan, John F. Fowler, Mary J. Lindstrom, and
R.  Timothy Mulcahy. Tamoxifen-induced Increase in the Potential Doubling Time of MCF-7 Xenografts as Determined by Bromodeoxyuridine Labeling and Flow Cytometry. CANCER RESEARCH 5.1. 4413-1417, September 15, 1993.
[3] Osborne CK.  Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998 Nov 26;339(22):1609-18.


Increased expression of estrogen receptor beta mRNA in tamoxifen-resistant breast cancer patients.[Pubmed:10554009]

Cancer Res. 1999 Nov 1;59(21):5421-4.

Tamoxifen is currently the first-line therapy for treatment of hormone-dependent breast cancer. However, despite initial benefits, most patients eventually relapse. Two groups of patients were identified: (a) a Tamoxifen-sensitive group (n = 8); and (b) a Tamoxifen-resistant group (n = 9). Using reverse transcription-PCR, the relative expression of mRNA for both estrogen receptor (ER) beta and transforming growth factor beta1 was determined in each patient group and quantified against a known reference standard. ER-beta mRNA was significantly up-regulated in the Tamoxifen-resistant group as compared with the Tamoxifen-sensitive group (P = 0.001 by Fisher's exact test), and, consistent with previous findings, transforming growth factor beta1 was also up-regulated in the Tamoxifen-resistant cohort (P = 0.02). The importance of ER-beta in Tamoxifen resistance was validated using Tamoxifen-sensitive and -resistant cell lines, in which it was demonstrated that ER-beta mRNA was significantly up-regulated in the resistant cells. These results lend further support to a role for ER-beta as a poor prognostic factor in breast cancer.

Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats.[Pubmed:3455628]

J Bone Miner Res. 1987 Oct;2(5):449-56.

To determine whether the nonsteroidal antiestrogen Tamoxifen behaves as either an agonist or antagonist of estrogen on bone, the effects of ovariectomy, 17 beta-estradiol, and Tamoxifen were compared on radial growth at the tibial diaphysis in young adult female rats. Ovariectomy and 17 beta-estradiol did not alter serum calcium, phosphate, or 25-hydroxyvitamin D. Ovariectomy increased serum 1,25-dihydroxyvitamin D in one experiment but not in the other. Tamoxifen increased the serum calcium and phosphate by itself and did not change serum 1,25-dihydroxyvitamin D in ovariectomized rats. Ovariectomy produced significant increases in medullary area, periosteal bone formation rate, and periosteal bone apposition rate compared to values in sham-operated animals and did not change endosteal bone formation rate. The increase in medullary area resulted from an increase in osteoclast number and resorbing surface length. Although endosteal forming surface length decreased, this was compensated for by an increase in the apposition rate. 17 beta-estradiol and Tamoxifen each prevented the increases in bone formation rate and medullary area in ovariectomized rats. Tamoxifen reduced the length of the resorbing surface and osteoclast number to values observed in sham-operated animals. The findings demonstrate that in the rat, Tamoxifen acts as an estrogen agonist by preventing the skeletal alterations that result from ovarian hormone deficiency.

Tamoxifen (ICI 47699) is a selective estrogen receptor modulator (SERM) which blocks estrogen action in breast cells and can activate estrogen activity in other cells, such as bone, liver, and uterine cells. Tamoxifen is a potent Hsp90 activator and enhances the Hsp90 molecular chaperone ATPase activity. Tamoxifen activates autophagy and induces apoptosis.

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