Comparative differential cytotoxicity of clinically used SERMs in human cancer lines of different origin and its predictive molecular docking studies of key target genes involved in cancer progression and treatment responses

Abstract

SERMS like Tamoxifene, 5-hydroxy tamoxifene, raloxifene and endoxifene has been used for the treatment of hormonal imbalances and dependent cancers owing to their action via Estrogen receptors as in the treatment of estrogen sensitive breast cancers. Due to the adverse side effects, modifications and development of the existing or newer SERMS has always been of immense interest. Ormeloxifene, a SERM molecule manufactured by HLL Lifecare Ltd, India as birth control under the trade names Saheli, Novex, and Novex-DS which is also investigated against mastalgia, fibro-adenoma and abnormal uterine bleeding. Anti-cancer effects have been reported in estrogen dependent and independent cancers which shows its wide scope to be implemented in cancer therapy. Current investigation is a comprehensive effort to find the cytotoxic potential of Ormeloxifene in comparison with clinically used four SERMS in twenty six cancer cell lines of different origin using Adriamycin as positive control. Also the computational studies pertaining to selected target/ligand with respect to tumor progression, development, treatment responses and apoptosis. The studies proved effective cytotoxicity of Ormeloxifene on cancer cell lines with lower TGI, GI50 and LC₅₀ values which are significantly comparable. Also the in silico studies proved that the docking score of the compound suggests the interaction of the compound which could tightly regulate key target genes controlling cancer like ER, EGFR kinase, EGFR-cSRC, HDAC-2, PARP-1 and BRAF. This study brings out the superior efficacy of Ormeloxifene compared to other SERMS with proven safety profile to be repositioned as an anti-cancer drug to treat diverse cancer types.

Keywords: 5-Hydroxy tamoxifene; Cytotoxicity; Endoxifene; Ormeloxifene; Raloxifene; SERM (Selective estrogen receptor modulator); Tamoxifene.

Graphical abstract

Fig. 1

Phase contrast microscopic images of cells showing the morphological differences in control Vs treated cells on different cell lines: (I.MCF-7, II. MDAMB-231, III. T-47D) cancer cell lines (A) Untreated Control cells, Cells treated with (B) Endoxifene, (C) Hydroxy tamoxifene), (D) Tamoxifene, (E) Ormeloxifene HCL, (F) Raloxifene, (G) Adriamycin treated positive control.

Fig. 1

Phase contrast microscopic images of cells showing the morphological differences in control Vs treated cells on different cell lines: (I.MCF-7, II. MDAMB-231, III. T-47D) cancer cell lines (A) Untreated Control cells, Cells treated with (B) Endoxifene, (C) Hydroxy tamoxifene), (D) Tamoxifene, (E) Ormeloxifene HCL, (F) Raloxifene, (G) Adriamycin treated positive control.

Fig. 1

Phase contrast microscopic images of cells showing the morphological differences in control Vs treated cells on different cell lines: (I.MCF-7, II. MDAMB-231, III. T-47D) cancer cell lines (A) Untreated Control cells, Cells treated with (B) Endoxifene, (C) Hydroxy tamoxifene), (D) Tamoxifene, (E) Ormeloxifene HCL, (F) Raloxifene, (G) Adriamycin treated positive control.

Fig. 1

Phase contrast microscopic images of cells showing the morphological differences in control Vs treated cells on different cell lines: (I.MCF-7, II. MDAMB-231, III. T-47D) cancer cell lines (A) Untreated Control cells, Cells treated with (B) Endoxifene, (C) Hydroxy tamoxifene), (D) Tamoxifene, (E) Ormeloxifene HCL, (F) Raloxifene, (G) Adriamycin treated positive control.

Fig. 1

Phase contrast microscopic images of cells showing the morphological differences in control Vs treated cells on different cell lines: (I.MCF-7, II. MDAMB-231, III. T-47D) cancer cell lines (A) Untreated Control cells, Cells treated with (B) Endoxifene, (C) Hydroxy tamoxifene), (D) Tamoxifene, (E) Ormeloxifene HCL, (F) Raloxifene, (G) Adriamycin treated positive control.

Fig. 1

Phase contrast microscopic images of cells showing the morphological differences in control Vs treated cells on different cell lines: (I.MCF-7, II. MDAMB-231, III. T-47D) cancer cell lines (A) Untreated Control cells, Cells treated with (B) Endoxifene, (C) Hydroxy tamoxifene), (D) Tamoxifene, (E) Ormeloxifene HCL, (F) Raloxifene, (G) Adriamycin treated positive control.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig 2

Prostate (PC-3, DU-145) and ovarian (SK-OV-3, A-2780) cancer cell lines (A) PC-3 (B) DU-145 (C) SK-OV-3 (D) A-2780 cell lines treated with 10,20,40 and 80 μg/ml of ormeloxifene, hydroxy tamoxifene, raloxifene, tamoxifene, enoxifene and adriamycin.

Fig. 3A

2D representation of molecular interaction of ormeloxifene and tamoxifene with targets 4MXO and 5WS1. D 5WS1 interaction with Tamoxifene. C 5WS1 interaction with Ormeloxifene. B 4MXO interaction with Tamoxifene. A 4MXO interaction with Ormeloxifene. 2D Interaction of ormeloxifene and tamoxifene with its critical amino acid residues in the receptors with (A,B) 4MXO (C,D) 5WS1.

Fig. 3B

2D representation of molecular interaction of ormeloxifene and tamoxifene with targets 2FB8 and 5UGA. D 5UGA interaction with Tamoxifene. C 5UGA interaction with Ormeloxifene. B 2FB8 interaction with Tamoxifene. A 2FB8 interaction with Ormeloxifene.2D Interaction of ormeloxifene and tamoxifene with active site amino acid residues of the receptors (A,B) 2FB8 (C,D) 5UGA.

Fig. 3C

2D representation of molecular interaction of ormeloxifene and tamoxifene with targets 3ERT and 5IWG. D 5IWG interaction with Tamoxifene. C 5IWG interaction with Ormeloxifene. B 3ERT interaction with Tamoxifene. A 3ERT interaction with Ormeloxifene. 2D Interaction of ormeloxifene and tamoxifene with active site amino acid residues of the receptors (A,B) 3ERT (C,D) 5IWG.

Fig. 4A

3D representation of molecular interaction of ormeloxifene with targets Interaction of ormeloxifene with receptors 4MXO and 5WS1. B 5WS1 interaction with Ormeloxifene. A 4MXO interaction with Ormeloxifene. 3D Interaction of ormeloxifene with active site amino acid residues of the receptors (A) 4MX0 (B) 5WS1. Ormeloxifene interacted with its active amino acids in the pockets EGFR cSRC and PARP-1respectively.

Fig. 4B

3D representation of molecular interaction of ormeloxifene with targets Interaction of ormeloxifene with receptors 3ERT and 5IWG. 3D Interaction of ormeloxifene with active site amino acid residues of the receptors (A) 3ERT (B) 5IWG. Ormeloxifene interacted with its active amino acids in the pockets ERα and HDAC2 respectively.

Fig. 4C

3D representation of molecular interaction of ormeloxifene with targets Interaction of ormeloxifene with receptors (A) 2FB8 and 5UGA. 3D Interaction of ormeloxifene with active site amino acid residues of the receptors (A) 2FB8 (B) 5UGA. Ormeloxifene interacted with its active amino acids in the pockets BRAF and EGFR kinase respectively.