Novel triterpenoid AECHL-1 induces apoptosis in breast cancer cells by perturbing the mitochondria–endoplasmic reticulum interactions and targeting diverse apoptotic pathways

• Published in: Biochimica et biophysica acta Vol. 1860; no. 6; pp. 1056 - 1070
• Main Authors: Sawant, Mithila A., Dasgupta, Aparajita, Lavhale, Manish S., Sitasawad, Sandhya L.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2016
• Subjects: adenocarcinoma; AECHL-1; AIF; Animals; antineoplastic activity; antineoplastic agents; apoptosis; Apoptosis - drug effects; breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcium; Calcium - physiology; caspases; Caspases - physiology; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; drug therapy; Endoplasmic Reticulum Stress - drug effects; epithelial cells; ER stress; Female; flow cytometry; Humans; immunohistochemistry; mammary glands; mechanism of action; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - physiology; neoplasm cells; phosphorylation; proteins; Reactive Oxygen Species - metabolism; Redox regulation; reticulum; severe combined immunodeficiency; toxicity; Triterpenes - pharmacology; triterpenoids; Western blotting; DHE; AECHL-1; 4-PBA; Calcium; Redox regulation; ER stress; ISRIB; PERK; TMRE; ER; eIF2α; Mitochondria; Nrf2; ROS; GSH; ZDF; AIF
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.02.002

The modus operandi for an anti-cancer drug must allow for an efficient discrimination system between tumorigenic and non-tumorigenic cells. Targeting ER stress and mitochondrial function in cancer cells appears to be a suitable option, as these processes are dysregulated in tumor cells. AECHL-1, a novel triterpenoid, exhibits potent anticancer activity against an array of cancer cell lines however, its mechanism of action remains elusive. Molecular targets of AECHL-1 were investigated using breast adenocarcinoma cells MCF-7, MDA-MB-231 and mammary epithelial cell line MCF 10A in vitro and xenograft tumors in SCID mice in vivo. Western blotting, flow cytometry, and immunohistochemical studies were employed to delineate the molecular pathways. AECHL-1 caused a transient elevation of ER stress proteins along with a prolonged phosphorylation of eIF2α in breast cancer cells. This was accompanied by a simultaneous release of calcium from ER stores and subsequent mitochondrial accumulation. These effects could be reversed by using ER stress inhibitors. AECHL-1 brings about mitochondria mediated, caspase independent cell death via AIF in MCF-7 cells; MDA-MB-231 succumbed to caspase dependent extrinsic pathway. Xenograft studies closely echoed our in vitro results. AECHL-1 did not alter cellular and molecular parameters in MCF 10A. These findings reveal that, AECHL-1 targets the Achilles Heel of cancer cell, namely dysfunctional ER and mitochondria while being non toxic to normal parenchyma and can thus be further explored as a potential chemotherapeutic intervention. Aggravation of ER stress by AECHL-1 uncovers a novel pathway for selective elimination of cancer cells. [Display omitted] •Molecular mechanism of an anticancer triterpenoid AECHL-1 is revealed.•Upregulated ER stress by AECHL-1 is implicated in killing of breast cancer cells.•Anticancer activity of AECHL-1 is driven via mitochondrial calcium accumulation.•MCF-7 cells succumb to mitochondrial dysfunction and AIF mediated apoptosis.•AECHL-1 targets MDA-MB-231cells by activation of extrinsic apoptotic pathway.