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Year : 2022  |  Volume : 12  |  Issue : 2  |  Page : 72-78

Antiproliferative Effects of Olanzapine against MCF-7 Cells and Its Molecular Interactions with Survivin

1 Department of Pharmacology, ESIC Medical College & PGIMSR, KK Nagar, Chennai, Tamil Nadu, India
2 PJ Biousys, Irving, TX, USA
3 Department of Pharmacology, MVJ Medical College and Research Hospital, Hoskote, Bangalore, Karnataka, India
4 Department of Pharmacology, SRMC & RI, Sri Ramachandra Institute of Higher Education and Research Institute, Porur, Chennai, Tamil Nadu, India
5 Department of Biotechnology, Dr MGR Educational and Research Institute, Maduravoyal, Chennai, Tamil Nadu, India
6 Department of Chemistry, Bapatla Engineering College (Autonomous), Acharya Nagarjuna University Post Graduate Research Centre, Bapatla, Andhra Pradesh, India
7 Department of Physics, University of Kerala, Thushara, Neethinagar, Kollam, Kerala, India

Date of Submission25-Dec-2021
Date of Decision15-Jan-2022
Date of Acceptance30-Jan-2022
Date of Web Publication10-May-2022

Correspondence Address:
Mohan Krishna Ghanta
MVJ Medical College and Research Hospital, Hoskote, Bangalore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijnpnd.IJNPND_82_21

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Background: Epidemiologic findings revealed approximately one-third of patients with breast cancer develop brain metastases. Recent research has found that schizophrenia patients who take antipsychotic medications on a long-term basis have a decreased risk of cancers than normal individuals. This serendipitous anticancer action of antipsychotic medications is now being investigated by many studies. The ability of these drugs to penetrate the blood–brain barrier may target brain metastases. We investigated antiproliferative activity of antipsychotic drug. The present study aimed to determine the antiproliferative effects of olanzapine against MCF-7 cells and also to examine its molecular interactions with survivin. Methods: The antiproliferative effects of olanzapine were demonstrated using MTT assay and molecular interactions were analyzed using AutoDock Vina ver4.0 between olanzapine (PubChem CID − 135398745) and survivin (PDB ID − 1E31). These molecular interactions were also compared with tamoxifen (PubChem CID: 2733526). Results: We found that olanzapine has extensive antiproliferative effects against MCF-7 human breast cancer cells, with an IC50 of 10.9 g/mL. We also discovered that olanzapine had possible interactions with the survivin protein at Lys15, Phe86, and Val89 amino acid residues, which could be related to effects of olanzapine on MCF-7 cell viability. Conclusion: Our research establishes that olanzapine has promising anticancer properties against breast tumors, with prospective application to target brain metastases in patients with breast cancer.

Keywords: Anticancer property, brain metastasis, MTT assay, olanzapine, tamoxifen

How to cite this article:
Varahi Vedam V, Nuthalapati P, Ghanta MK, David D, Vijayalakshmi M, Potla K, Mary Y. Antiproliferative Effects of Olanzapine against MCF-7 Cells and Its Molecular Interactions with Survivin. Int J Nutr Pharmacol Neurol Dis 2022;12:72-8

How to cite this URL:
Varahi Vedam V, Nuthalapati P, Ghanta MK, David D, Vijayalakshmi M, Potla K, Mary Y. Antiproliferative Effects of Olanzapine against MCF-7 Cells and Its Molecular Interactions with Survivin. Int J Nutr Pharmacol Neurol Dis [serial online] 2022 [cited 2022 Oct 1];12:72-8. Available from:

   Introduction Top

Breast cancer is one of the specific cancers that have a high incidence of metastasis.[1] Higher incidences of brain metastasis in patients with breast cancer were diagnosed in recent years. [2,3] In this scenario, there is more need for anticancer drugs that can reach the central nervous system. [1, 4, 5] Currently, antipsychotic drugs are being investigated for their anticancer potential against breast cancer, brain metastasis, and other cancer types as well. The pathways targeted by these drugs include inhibition of histone deacetylases, deubiquitination complex, and phosphoinositide 3-kinase pathway. These properties of antipsychotics make them suitable candidates for drug repurposing. The drug repurposing of antipsychotic drugs for treating breast cancer may provide new effective cancer therapeutics with a shorter time frame of the drug discovery process.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21] Olanzapine, as an antipsychotic drug, has proven antagonistic actions on dopamine D2 receptors (DRD2) and serotonin receptors (5-HT2A).[21] Downregulation of DRD2 and 5-HT2A receptor activities were found beneficial in cancer chemotherapeutics. The DRD2 antagonism modulates the cyclic adenosine monophosphate (cAMP) pathway, epidermal growth factor receptor signaling, Wnt signaling, and calcium signaling pathways.[22] The 5-HT2A receptors modulate the beta-catenin pathway, cAMP pathway, and angiogenesis in tumor cells.[23],[24],[25] All these pathways influenced by DRD2 and 5-HT2A receptors affect survivin expression.[26],[27],[28],[29],[30]

Olanzapine treatment against lung, pancreatic cancer stem cells, and ovarian cancer cells made them more sensitive to anticancer drugs through survivin inhibition. Survivin is an antiapoptotic molecule and mitosis inducer as well. The accumulation of mitosis in a cell cycle was positively correlated to upregulated survivin expression and its inhibition could be a possible target for the treatment of breast cancer, lung cancer, and ovarian carcinoma.[31],[32],[33] Therefore, the aim of this study is to assess the in vitro antiproliferative property of olanzapine against MCF-7 cells, and also to predict the molecular interaction of olanzapine with survivin using the in silico molecular docking method.

   Materials and Methods Top

Chemicals and reagents

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide (MTT), cell culture reagents, and chemicals were obtained from Himedia Pvt Ltd (Mumbai, Maharashtra, India) and Tokyo Chemical Industry (Chennai, Tamil Nadu, India).

Cell culture

MCF-7 cells (NCCS, Pune, India) were cultured in minimum essential medium (MEM) containing 10% fetal bovine serum, 5% CO2, and incubated at 37°C with appropriate humidity. After observation for healthy cultured cells, the culture flask is split, then the media is discarded and the cells were subjected to 2× wash with MEM. Following this, the cells were incubated in trypsin phosphate versene glucose (TPVG) phosphate buffer saline for 1 minute, later TPVG was discarded, and the 10% MEM was added. The cells were passaged and shifted to 96 well-plates.

MTT assay

The MCF-7 cells were seeded in 96-well plates and incubated for 24 hours before being treated with olanzapine at various concentrations. The media was replaced every 2 days, and the cells were then washed and exposed to MTT salts using a standard procedure on the third day (72 hours).[34] The absorbance at 540 nm was used to determine the viability of the cells. The cell viability–concentration plot yielded the 50% cell viability (IC50) value. The % cell viability is given by[35]

Molecular docking

To find candidate drugs for survivin inhibition property, we have carried out a computational study to screen for effective drugs, endoxifen (PubChem CID:10090750), tamoxifen (PubChem CID: 2733526), and olanzapine (PubChem CID: 135398745) which may work as an inhibitor for apoptosis.[36] The structure of survivin (PDB ID: 1E31) was obtained from the Protein Data Bank (PDB) database, and molecular docking was performed with AutoDock Vina ver4.0 and as in literature.[37],[38],[39]

   Results Top

Olanzapine inhibits MCF-7 cell proliferation

The antiproliferative property of olanzapine was screened using MTT assay. The percentage cell viability–concentration graph trendline showed a dose-dependent steep fall in MCF-7 cell viability with an increase in the dose of olanzapine. The IC50 concentration of olanzapine in breast cancer cell lines was 10.9 μg/mL, indicating sensitivity to the drug [Figure 1] and [Figure 2]].
Figure 1 MCF-7 cell morphology in MTT assay with inverted microscope at 40× magnification. (a) MCF-7 morphology with 25 μg/mL olanzapine, (b) MCF-7 morphology with 12.5 μg/mL olanzapine, (c) MCF-7 morphology with 6.25 μg/mL olanzapine, (d) MCF-7 morphology with 3.12 μg/mL olanzapine, (e) control cells, (f) DMSO control cells.

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Figure 2 Effect of olanzapine on MCF-7 cell survival as established by MTT assay. Graphical representation of IC50 of olanzapine against MCF-7 cells depicted in green color at 10.9 μg/mL.

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Molecular interactions of ligands with survivin

In silico screening was performed to evaluate the inhibition of survivin by olanzapine. Tamoxifen and its metabolite endoxifen were also selected for comparison. The binding energy of the three compounds at different root-mean-square deviations (RMSD) is depicted in [Figure 3]. In this study, RMSD was set to 0 Å.
Figure 3 Binding energy of ligands at distance from best mode (Å) with codons of survivin. Y-axis represents binding energy (kcal/mol). X-axis represents modes. RMSD LB and RMSD UB − root mean square deviation upper and lower bound. BE, binding energy. (a) Endoxifen, (b) tamoxifen, (c) olanzapine.

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Interactions of endoxifen with 1E31

At the ranges of 2.42, 2.66, and 2.78 Å, the amino acid ASP16 forms two salt-bridge H-bonds with the same NH2 group and a carbon–hydrogen (C–H) bond with the methylene group. GLN92, PHE93 show ‐-donor H-bond with RingI, RingIII centers at the distances of 4.18 Å and 3.77 Å, whereas GLU40 has an electrostatic ‐-anion interaction with RingI at the distance 3.57 Å. VAL89, PHE93, formulate hydrophobic ‐-sigma, hydrophobic ‐-‐ T-shaped, hydrophobic ‐-alkyl interactions, respectively, with RingII having the distances 3.83, 5.63, and 5.26 Å. The RingI and RingIII exist at distances of 4.90 and 5.13 Å with LYS15, exhibiting two hydrophobic-‐-alkyl interactions. At a distance of 4.32 Å, PHE86 exhibits a hydrophobic--alkyl linking to the methyl group [[Figure 4]].{Figue 4}

Interactions of tamoxifen with 1E31

At ranges of 2.18 and 4.90 Å, the amino acid VAL89 forms a typical H-bond with the NH group and hydrophobic- -alkyl linkages with the RingIII center. At 2.86 Å, PHE86 forms C–H linkages with the methyl ester, whereas Glu40 exhibits an electrostatic- -anion linking with the RingIII center at 4.03 Å. Lys15 formulates hydrophobic- -sigma interaction with RingI and hydrophobic-alkyl linkages to methyl esters at 3.66 and 5.28 Å. PHE93 exhibited t-shaped hydrophobic- - linkages with RingII at 5.76 Å [[Figure 4]].

Interactions of olanzapine with 1E31

The amino acids LYS15 and VAL89 forming hydrophobic alkyl interactions with RingIII and RingI center, respectively, are at the distances of 4.12 and 4.73 Å. Phe86 shows hydrophobic -alkyl interactions with RingI center at the distance of 4.64 Å [[Figure 4]].

   Discussion Top

Our study establishes the in vitro antiproliferative effects of olanzapine against breast cancer MCF-7 cells, which may be beneficial as an adjuvant in the treatment of brain metastasis. Olanzapine exhibited dose-dependent cytotoxicity in MTT assay. The apoptosis induced through mitochondrial complex I pathway[40] is well studied using MTT assay by previous studies[41] and relates antiproliferative actions of olanzapine in MCF-7 cells.

Molecular interactions of olanzapine against survivin were also demonstrated in our study. Survivin is a dimeric protein and its dimerization interface was the target site for inhibition of its activity. The dimerization sites of survivin constitute 6–10, 93–99, 101, and 102 amino acid residues. Another important site of survivin for regulating its activity is the linker segment of monomer which comprises valine 89 to threonine 97 codon. Tamoxifen and its metabolite endoxifen interacted with both dimerization interface and linker segment codons, whereas olanzapine interacted only with linker segment codons. Thus, these interactions signify the inhibition of survivin by the three compounds of the study.

The binding efficacy of olanzapine to survivin was comparable to endoxifen, a metabolite of tamoxifen, and approximate to tamoxifen. Olanzapine exhibited good binding affinities with Lys15, Val89, and Phe86. Similar interactions were also observed with tamoxifen and its metabolite endoxifen. Other ligands that were evaluated as potential survivin inhibitors showed molecular interactions with the same amino acid residues. With survivin protein, ZINC00689728 had a −9.3 kcal/mol binding energy and hydrophobic interactions with Phe93, Val89, and Phe86 residues.[42] The S12 enantiomer, which was anticipated as the dynamic isomer inhibiting survivin, showed interactions with amino acids Lys15, Phe86, Phe93, and Val89.[43] Similar interactions were found with LQZ-7, which triggered spontaneous apoptosis against several cancer cells without affecting the synthesis of survivin.[43] LQZ-7-induced survivin degradation was based on the concept that exposing a dimeric protein’s hydrophobic interface causes conformational changes [44,45] which promote protein instability and breakdown by autophagy or proteasome.[46] Andrographolide interacting with Thr34 and Glu36 of human survivin in silico was shown to possess in vitro cytotoxicity activity with cytotoxicity concentration-50 of 0.32 mM against breast tumor cells.[47]

   Conclusion Top

Thus, we demonstrated the anticancer property of olanzapine with its in silico molecular interactions against survivin and enhanced cytotoxicity to MCF-7 cells in vitro. We suggest that the binding of olanzapine to survivin at Phe86, Val89, and Lys15 amino acid residues may be the critical part of the effects of olanzapine. Therefore, olanzapine may be a potential adjuvant anticancer therapy in breast cancer which could be beneficial for targeting brain metastasis.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

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