Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

Abstract

We have earlier reported anticancer activity in Withaferin A (Wi-A), a withanolide derived from Ashwagandha (Withania somnifera) and caffeic acid phenethyl ester (CAPE), an active compound from New Zealand honeybee propolis. Whereas Wi-A was cytotoxic to both cancer and normal cells, CAPE has been shown to cause selective death of cancer cells. In the present study, we investigated the efficacy of Wi-A, CAPE, and their combination to ovarian and cervical cancer cells. Both Wi-A and CAPE were seen to activate tumor suppressor protein p53 by downregulation of mortalin and abrogation of its interactions with p53. Downregulation of mortalin translated to compromised mitochondria integrity and function that affected poly ADP-ribose polymerase1 (PARP1); a key regulator of DNA repair and protein-target for Olaparib, drugs clinically used for treatment of breast, ovarian and cervical cancers)-mediated DNA repair yielding growth arrest or apoptosis. Furthermore, we also compared the docking capability of Wi-A and CAPE to PARP1 and found that both of these could bind to the catalytic domain of PARP1, similar to Olaparib. We provide experimental evidences that (i) Wi-A and CAPE cause inactivation of PARP1-mediated DNA repair leading to accumulation of DNA damage and activation of apoptosis signaling by multiple ways, and (ii) a combination of Wi-A and CAPE offers selective toxicity and better potency to cancer cells.

Computational Insights into the Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl Ester for Treatment of Aberrant-EGFR Driven Lung Cancers

“…Natural medicine such as Ashwagandha and honeybee propolis have been used for centuries for prevention and cure of multiple chronic and infectious diseases [ 41 , 71 , 72 ]. The anticancer activities of non-toxic dose of natural drugs such as Wi-A and Wi-N from Ashwagandha and CAPE from honeybee propolis have been reported through various mechanisms in the literature [ 34 , 36 , 73 , 74 ]. The selective inhibition of cancer cells has also been shown by the alcoholic leaf extract of Ashwagandha and Wi-N via ROS signaling [ 75 ].…”

“…Scientifically known as Withania somnifera , it possesses aphrodisiac, adaptogenic, rejuvenative, anti-inflammatory and anticancer properties [ 26 ] that have been assigned to its secondary metabolites, e.g., alkaloids, steroidal lactones and saponins. Wi-N and Wi-A have been reported to have anticancer activities that works through the inhibition of Mortalin-p53 interactions leading to activation of tumor suppressor activities of p53, downregulation of NFkB leading to inhibition of inflammation signaling, inhibition of MRN complex leading to accumulation of DNA damage and growth arrest of cancer cells and inhibition of VEGF and MMPs leading to inactivation of cancer cell migration and metastasis [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. It has also been reported through cell culture assays that Wi-A induced apoptosis in NSCLC having both wildtype and mutant forms of EGFR [ 37 ].…”

“…In addition, Wi-A in combination with glucose metabolism targeted therapy was able to inhibit gefitinib resistant lung cancer cell lines [ 38 ]. Similarly, Caffeic Acid Phenethyl Ester (CAPE), a bioactive component from honeybee propolis, has been shown to possess anticancer and anti-metastasis activities through various mechanisms [ 34 , 39 , 40 , 41 , 42 , 43 , 44 ]. Several in vitro and in vivo based studies showed that CAPE and its derivatives can inhibit EGFR signaling pathway through downregulation of expression level of EGFR and phosphorylated EGFR proteins [ 45 , 46 ].…”

Detection of Ovarian Cancer through Exhaled Breath by Electronic Nose: A Prospective Study

“…Further large prospective studies are needed to confirm our data. OC represents a group of heterogeneous diseases [35][36][37][38][39][40]; therefore, further investigations are needed to evaluate the applicability of e-nose in detecting various OC types. The new perspective is the implementation of this device in the new collection of exhaled breath samples on a larger population to validate these results and build more robust classification models.…”

Anticancer Mechanism of Withania Somnifera and Its Bioactive Compounds : A Short Review Along with Computational Molecular Docking Study

“…Ethanol extract of Withania somnifera downregulated the expression of fatty acid metabolism proteins [ACLY, ACC1, FASN, CPT1A] and inhibited fatty acid synthesis in LNCaP, 22Rv1 cell lines, suggesting proliferative activity of WS [45]. A recent study suggested that Withaferin-A reduced the regulation of mortalin and PARP1 and induced the regulation of tumor suppressor p53 and DNA damage signaling in cancer cells [46]. Combined treatment of Doxorubicin with Withaferin-A was found to increase the level of ROS production resulting in increasing the expression of autophagy marker LC3B; inhibit cell proliferation and induce cell death [47].…”