Centchroman induces redox-dependent apoptosis and cell-cycle arrest in human endometrial cancer cells.
Centchroman (CC) or Ormeloxifene has been shown to induce apoptosis and cell cycle arrest in various types of cancer cells. This has, however, not been addressed for endometrial cancer cells where its (CC) mechanism of action remains unclear. This study focuses on the basis of antineoplasticity of CC by blocking the targets involved in the cell cycle, survival and apoptosis in endometrial cancer cells. Ishikawa Human Endometrial Cancer Cells were cultured under estrogen deprived medium, exposed to CC and analyzed for proliferation and apoptosis. Additionally, we also analyzed oxidative stress induced by CC. Cell viability studies confirmed the IC50of CC in Ishikawa cells to be 20 µM after 48 h treatment. CC arrests the cells in G0/G1 phase through cyclin D1 and cyclin E mediated pathways. Phosphatidylserine externalization, nuclear morphology changes, DNA fragmentation, PARP cleavage, and alteration of Bcl-2 family protein expression clearly suggest ongoing apoptosis in the CC treated cells. Activation of caspase 3 & 9, up-regulation of AIF and inhibition of apoptosis by z-VAD-fmk clearly explains the participation of the intrinsic pathway of programmed cell death. Further, the increase of ROS, loss of MMP, inhibition of antioxidant (MnSOD, Cu/Zn-SOD and GST) and inhibition of apoptosis with L-NAC suggests CC induced oxidative stress leading to apoptosis via mitochondria mediated pathway. Therefore, CC could be a potential therapeutic agent for the treatment of Endometrial Cancer adjunct to its utility as a contraceptive and an anti-breast cancer agent.
Division of Biochemistry, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, 226031, Lucknow, India.|Department of Molecular Biology, Centre for Advance Research, King George's Medical University, 226 003, Lucknow, India.
Hari
H
Shyam
Department of Molecular Biology, Centre for Advance Research, King George's Medical University, 226 003, Lucknow, India.
Neetu
N
Singh
Division of Biochemistry, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, 226031, Lucknow, India.
Shweta
S
Kaushik
Division of Biochemistry, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, 226031, Lucknow, India.
Ramesh
R
Sharma
Division of Biochemistry, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, 226031, Lucknow, India. anilbalapure58@gmail.com.
Anil K
AK
Balapure
D000230:Adenocarcinoma / Q000473:pathology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002486:Centchroman / Q000494:pharmacology*; D019938:Cyclin D1 / Q000502:physiology; D019927:Cyclin E / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009363:Neoplasm Proteins / Q000502:physiology; D010084:Oxidation-Reduction; D021381:Protein Transport / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D009363:Neoplasm Proteins; D019938:Cyclin D1; D002486:Centchroman; D020169:Caspases
Apoptosis; Centchroman; Endometrial cancer; Ishikawa cells; Ormeloxifene; Oxidative stress