Eck K M, Yuan L, Duffy L, Ram P T, Ayettey S, Chen I, Cohn C S, Reed J C, Hill S M
Department of Anatomy, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Br J Cancer. 1998 Jun;77(12):2129-37. doi: 10.1038/bjc.1998.357.
Neoplastic events are marked by uncontrolled cell proliferation. One major focus of cancer research has been to identify treatments that reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been used to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. Using the oestrogen receptor (ER)-positive MCF-7 human breast tumour cell line, our laboratory has studied the effects of a sequential treatment regimen of melatonin followed by all-trans retinoic acid (atRA) on breast tumour cell proliferation in vitro. Incubation of hormonally responsive MCF-7 and T47D cells with melatonin (10(-9) M) followed 24 h later by atRA (10(-9) M) resulted in the complete cessation of cell growth as well as a reduction in the number of cells to below the initial plating density. This cytocidal effect is in contrast to the growth-suppressive effects seen with either hormone alone. This regimen of melatonin followed by atRA induced cytocidal effects on MCF-7 cells by activating pathways leading to apoptosis (programmed cell death) as evidenced by decreased ER and Bcl-2 and increased Bax and transforming growth factor beta 1 (TGF-beta1) expression. Apoptosis was reflected morphologically by an increase in the number of lysosomal bodies and perinuclear chromatin condensation, cytoplasmic blebbing and the presence of apoptotic bodies. The apoptotic effect of this sequential treatment with melatonin and atRA appears to be both cell and regimen specific as (a) ER-negative MDA-MB-231 and BT-20 breast tumour cells were unaffected, and (b) the simultaneous administration of melatonin and atRA was not associated with apoptosis in any of the breast cancer cell lines studied. Taken together, the results suggest that use of an appropriate regimen of melatonin and atRA should be considered for preclinical and clinical evaluation against ER-positive human breast cancer.
肿瘤事件的特征是细胞不受控制地增殖。癌症研究的一个主要重点是确定能够减少或抑制细胞生长的治疗方法。多年来，各种天然存在的和化学合成的化合物都被用于抑制肿瘤细胞增殖。两种这样的抑癌剂，褪黑素和视黄酸，已被证明能抑制激素反应性乳腺癌的生长。目前，存在单独的临床方案用于将类视黄醇和褪黑素作为癌症的辅助治疗药物。利用雌激素受体（ER）阳性的MCF-7人乳腺肿瘤细胞系，我们实验室研究了褪黑素后接全反式视黄酸（atRA）的序贯治疗方案对体外乳腺肿瘤细胞增殖的影响。用褪黑素（10⁻⁹ M）孵育激素反应性MCF-7和T47D细胞，24小时后再用atRA（10⁻⁹ M）处理，导致细胞生长完全停止，并且细胞数量减少到初始接种密度以下。这种细胞杀伤作用与单独使用任何一种激素时所见的生长抑制作用形成对比。这种褪黑素后接atRA的方案通过激活导致凋亡（程序性细胞死亡）的途径对MCF-7细胞产生细胞杀伤作用，这表现为ER和Bcl-2减少以及Bax和转化生长因子β1（TGF-β1）表达增加。凋亡在形态学上表现为溶酶体数量增加、核周染色质凝聚、细胞质起泡以及凋亡小体的出现。褪黑素和atRA序贯治疗的凋亡作用似乎具有细胞和方案特异性，因为（a）ER阴性的MDA-MB-231和BT-20乳腺肿瘤细胞未受影响，并且（b）在任何研究的乳腺癌细胞系中，同时给予褪黑素和atRA均未导致凋亡。综上所述，结果表明，对于ER阳性的人乳腺癌的临床前和临床评估，应考虑使用适当的褪黑素和atRA方案。
