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p53-Dependent ENOX2 Downregulation Mediates the Apoptotic Responses to Heteroarene-Fused Anthraquinones in Colon
Chien-Yu Chen1, Alexander S Tikhomirov2, Yih-Farng Liou3
1Graduate Institute of Biomedical Sciences, College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan.
Abstract:
Anthraquinone-based intercalating compounds, such as doxorubicin and mitoxantrone, have long been used clinically due to their ability to induce DNA damage. More recently, heteroarene-fused anthraquinones have been developed to further enhance their anticancer activity. Among these compounds, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated as derivative a) was identified as a potent apoptotic inducer. Based on this scaffold, two additional derivatives were synthesized by replacing the sulfur atom within the heterocyclic ring with nitrogen (derivative b) or oxygen (derivative c). Building upon our previous identification of ENOX2 as the primary target of this scaffold, the present study investigated the antiproliferative effects and underlying mechanisms of these derivatives in colon cancer cells with varying p53 statuses. Derivatives a and b effectively induced apoptosis and suppressed proliferation in p53 wild-type HCT116 cells, which was concomitantly accompanied by significant ENOX2 downregulation and the activation of intrinsic apoptotic signaling. In contrast, p53-null HCT116 cells exhibited reduced sensitivity, attenuated apoptotic responses, and minimal ENOX2 downregulation. Notably, derivative c primarily induced G2/M arrest rather than apoptosis regardless of p53 status, indicating a predominantly cytostatic mechanism. Collectively, these findings suggest that the degree of ENOX2 modulation is linked to the distinct anti-proliferative responses induced by heteroarene-fused anthraquinones, and that p53 status serves as a critical molecular switch influencing the transition between cytostatic growth arrest and apoptotic cell death.
Insights
New anticancer compounds, heteroarene-fused anthraquinones, induce apoptosis by downregulating ENOX2 in colon cancer cells. P53 status dictates whether cells undergo apoptosis or cytostatic arrest.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Anthraquinone derivatives are clinically used anticancer agents that induce DNA damage.
- Heteroarene-fused anthraquinones represent a newer class with enhanced anticancer potential.
- ENOX2 (euthanasia and nuclease domain-containing protein 2) has been identified as a key target for this scaffold.
Purpose of the Study:
- To investigate the antiproliferative effects and mechanisms of novel heteroarene-fused anthraquinones (derivatives a, b, and c) in colon cancer cells.
- To determine the role of p53 status in mediating the cellular response to these compounds.
- To elucidate the relationship between ENOX2 modulation and the observed anti-cancer effects.
Main Methods:
- Synthesis of three heteroarene-fused anthraquinone derivatives (a, b, and c) with varying heterocyclic atoms (sulfur, nitrogen, oxygen).
- Treatment of colon cancer cell lines (HCT116 with wild-type and null p53) with the synthesized derivatives.
- Assessment of antiproliferative effects, apoptosis induction, cell cycle arrest, and ENOX2 expression levels.
Main Results:
- Derivatives a and b induced apoptosis and suppressed proliferation in p53 wild-type cells, correlating with ENOX2 downregulation and intrinsic apoptosis activation.
- p53-null cells showed reduced sensitivity, weaker apoptotic responses, and minimal ENOX2 modulation by derivatives a and b.
- Derivative c induced G2/M arrest (cytostatic effect) irrespective of p53 status, suggesting a different mechanism of action.
Conclusions:
- The degree of ENOX2 modulation by heteroarene-fused anthraquinones is linked to their distinct anti-proliferative activities.
- p53 status acts as a critical determinant in switching between cytostatic growth arrest and apoptotic cell death.
- These findings highlight the potential of targeting ENOX2 and considering p53 status for developing novel colon cancer therapeutics.
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02:23Abnormal Proliferation