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

被引：41

作者：

Sari, Anissa Nofita ^{[1
,2
]}

Bhargava, Priyanshu ^{[1
]}

Dhanjal, Jaspreet Kaur ^{[1
,3
]}

Putri, Jayarani F. ^{[1
]}

Radhakrishnan, Navaneethan ^{[3
]}

Shefrin, Seyad ^{[3
]}

Ishida, Yoshiyuki ^{[4
]}

Terao, Keiji ^{[4
]}

Sundar, Durai ^{[3
]}

Kaul, Sunil C. ^{[1
,2
]}

Wadhwa, Renu ^{[1
,2
]}

机构：

[1] Natl Inst Adv Ind Sci & Technol, DBT AIST Int Ctr Translat & Environm Res DAICENTE, DAILAB, Tsukuba, Ibaraki 3058565, Japan

[2] Univ Tsukuba, Sch Integrat & Global Majors, Tsukuba, Ibaraki 3058577, Japan

[3] Indian Inst Technol IIT Delhi, Dept Biochem Engn & Biotechnol, DAILAB, New Delhi 110016, India

[4] CycloChem Co Ltd, Chuo Ku, 7-4-5 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan

来源：

CANCERS | 2020年 / 12卷 / 05期

关键词：

Ashwagandha; Withaferin A; Honeybee propolis; CAPE; Cancer; Mortalin; p53; PARP1; Regulation; ACID PHENETHYL ESTER; CELL-CYCLE ARREST; CANCER-CELLS; INTERCELLULAR COMMUNICATION; MATRIX-METALLOPROTEINASE; GROWTH-INHIBITION; PARP INHIBITORS; APOPTOSIS; EXPRESSION; PROPOLIS;

D O I：

10.3390/cancers12051160

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：25