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Background <p>Breast cancer has the highest incidence among cancers in women, with estrogens playing a pivotal role in the estrogen receptor-positive (ER+) subtype. Local estrogen levels in breast tissue are regulated by enzymes involved in estrogen synthesis and metabolism. Our previous studies identified indole-based melatonin analogues as potent aromatase inhibitors, with 2-methyl-1&#xa0;H-indole-3-carboxaldehyde-(4-chlorophenyl)hydrazone (1j) being the most effective compound.</p> Objectives <p>This study aimed to evaluate the cytotoxic, anti-proliferative, anti-migrative, and estrogen receptor antagonist effects of in ER+ breast cancer models and to investigate its activity on CYP1B1, an estrogen-metabolizing enzyme. Furthermore, the potential tumor-suppressive effect of was assessed <i>in vivo</i> using a syngeneic ER+ murine breast cancer model.</p> Methods <p><i>In vitro</i> cytotoxicity and long-term survival were assessed via MTT and colony formation assays in MCF-7, 67NR, and MCF-10&#xa0;A cells. Cell migration was examined using a scratch assay. Estrogen receptor antagonist activity was measured through the E-Screen assay in MCF-7 BUS cells, while CYP1B1 inhibition was determined in rat microsomes and recombinant human CYP1B1. <i>In vivo </i>efficacy was tested in 67NR tumor-bearing mice treated with 1&#xa0;mg/kg body weight 1j.</p> Results <p>1j exhibited time- and dose-dependent cytotoxicity, significantly reducing the viability of 67NR and MCF-7 cells, while showing lower toxicity in MCF-10&#xa0;A cells. Colony formation assays revealed selective long-term inhibition in breast cancer cells. At sub-cytotoxic levels, 1j suppressed migration, reducing MCF-7 and 67NR cell movement by 64% and 86%, respectively. 1j antagonized ER-mediated proliferation with an IC<sub>50</sub> of 0.9 µM and potently inhibited CYP1B1 (IC<sub>50</sub> 0.052 µM), surpassing ketoconazole. However, <i>in vivo</i> administration did not significantly reduce tumor growth in the 67NR syngeneic model.</p> Conclusion <p>The indole-based melatonin analogue 1j demonstrated promising <i>in vitro</i> cytotoxic, anti-migrative, ER-antagonizing, and CYP1B1 inhibitory effects, supporting its potential as a therapeutic candidate for ER+ breast cancer. While <i>in vivo</i> tumor-suppressive activity was not observed under the tested regimen, further studies with optimized dosing and combination strategies are warranted.</p> Graphical Abstract <p></p>

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Beneficial effects of an indole derivative melatonin analogue in estrogen receptor positive breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Elif Ince-Erguc,
  • Alev Tascioglu Aliyev,
  • Kimberly Krager,
  • Sibel Suzen,
  • Nukhet Aykin-Burns,
  • Hande Gurer-Orhan

摘要

Background

Breast cancer has the highest incidence among cancers in women, with estrogens playing a pivotal role in the estrogen receptor-positive (ER+) subtype. Local estrogen levels in breast tissue are regulated by enzymes involved in estrogen synthesis and metabolism. Our previous studies identified indole-based melatonin analogues as potent aromatase inhibitors, with 2-methyl-1 H-indole-3-carboxaldehyde-(4-chlorophenyl)hydrazone (1j) being the most effective compound.

Objectives

This study aimed to evaluate the cytotoxic, anti-proliferative, anti-migrative, and estrogen receptor antagonist effects of in ER+ breast cancer models and to investigate its activity on CYP1B1, an estrogen-metabolizing enzyme. Furthermore, the potential tumor-suppressive effect of was assessed in vivo using a syngeneic ER+ murine breast cancer model.

Methods

In vitro cytotoxicity and long-term survival were assessed via MTT and colony formation assays in MCF-7, 67NR, and MCF-10 A cells. Cell migration was examined using a scratch assay. Estrogen receptor antagonist activity was measured through the E-Screen assay in MCF-7 BUS cells, while CYP1B1 inhibition was determined in rat microsomes and recombinant human CYP1B1. In vivo efficacy was tested in 67NR tumor-bearing mice treated with 1 mg/kg body weight 1j.

Results

1j exhibited time- and dose-dependent cytotoxicity, significantly reducing the viability of 67NR and MCF-7 cells, while showing lower toxicity in MCF-10 A cells. Colony formation assays revealed selective long-term inhibition in breast cancer cells. At sub-cytotoxic levels, 1j suppressed migration, reducing MCF-7 and 67NR cell movement by 64% and 86%, respectively. 1j antagonized ER-mediated proliferation with an IC50 of 0.9 µM and potently inhibited CYP1B1 (IC50 0.052 µM), surpassing ketoconazole. However, in vivo administration did not significantly reduce tumor growth in the 67NR syngeneic model.

Conclusion

The indole-based melatonin analogue 1j demonstrated promising in vitro cytotoxic, anti-migrative, ER-antagonizing, and CYP1B1 inhibitory effects, supporting its potential as a therapeutic candidate for ER+ breast cancer. While in vivo tumor-suppressive activity was not observed under the tested regimen, further studies with optimized dosing and combination strategies are warranted.

Graphical Abstract