Phytochemicals from Ajwa dates pulp extract induce apoptosis in human triple-negative breast cancer by inhibiting AKT/mTOR pathway and modulating Bcl-2 family proteins.

Mohsin Ali Khan,Sahabjada Siddiqui,Anand Narain Srivastava,Romila Singh,Imran Ahmad,Durga Prasad Mishra,Rumana Ahmad

doi:10.1038/s41598-021-89420-z

Abstract

Ajwa dates (Phoenix dactylifera L.) have been described in traditional and alternative medicine to provide several health benefits, but their mechanism of apoptosis induction against human triple-negative breast cancer MDA-MB-231 cells remains to be investigated. In this study, we analyzed the phytoconstituents in ethanolic Ajwa Dates Pulp Extract (ADPE) by liquid chromatography-mass spectrometry (LC–MS) and investigated anticancer effects against MDA-MB-231 cells. LC–MS analysis revealed that ADPE contained phytocomponents belonging to classes such as carbohydrates, phenolics, flavonoids and terpenoids. MTT assay demonstrated statistically significant dose- and time-dependent inhibition of MDA-MB-231 cells with IC50 values of 17.45 and 16.67 mg/mL at 24 and 48 h, respectively. Hoechst 33342 dye and DNA fragmentation data showed apoptotic cell death while AO/PI and Annexin V-FITC data revealed cells in late apoptosis at higher doses of ADPE. More importantly, ADPE prompted reactive oxygen species (ROS) induced alterations in mitochondrial membrane potential (MMP) in ADPE treated MDA-MB-231 cells. Cell cycle analysis demonstrated that ADPE induced cell arrest in S and G2/M checkpoints. ADPE upregulated the p53, Bax and cleaved caspase-3, thereby leading to the downregulation of Bcl-2 and AKT/mTOR pathway. ADPE did not show any significant toxicity on normal human peripheral blood mononuclear cells which suggests its safe application to biological systems under study. Thus, ADPE has the potential to be used as an adjunct to the mainline of treatment against breast cancer.

Highlights

Breast cancer is an abnormal growth of cells lining the breast lobules or ducts
Ajwa Dates Pulp Extract (ADPE) was found to be non-toxic without any associated morphological effects on peripheral blood mononuclear cells (PBMCs) (Fig. 2e and f), which suggests that ADPE is non-toxic to normal human cells
The present study revealed the potent growth-inhibitory effect of Ajwa dates pulp against human TNBC MDA-MB-231 cells with no significant toxic effect on normal human PBMCs

Summary

Introduction

Breast cancer is an abnormal growth of cells lining the breast lobules or ducts. These cells grow uncontrollably and have the potential to spread to other parts of the body. Treatment with insignificant adverse effects, killing cancer cells with minimal toxicity to normal cells may present as a practical approach for improving breast cancer therapy. Recent research has shown the anticancer potential of Ajwa dates extract in combination with 5-fluorouracil against human breast adenocarcinoma cell line MCF-79 and apoptosis-inducing effect and cell cycle arrest in prostate cancer cells P C310. None of the studies have, so for, reported the mechanism of anticancer action of Ajwa dates pulp extract by modulation of Bcl-2 family proteins and downregulation of AKT/mTOR signaling pathway in breast carcinoma MDA-MB-231 cells. ADPE was tested for its toxicity against normal human peripheral blood mononuclear cells (PBMCs)

Methods

Results

Discussion

Conclusion