A Lipid-Modified Estrogen Derivative that Treats Breast Cancer Independent of Estrogen Receptor Expression through Simultaneous Induction of Autophagy and Apoptosis

Abstract

It is a challenge to develop a universal single drug that can treat breast cancer at single or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific estrogen-based drugs are being developed which cannot act against multi-staged breast cancer complications owing to cells’ differential ER expression status and their possession of drug-resistant and metastatic phenotypes. We report here the development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their estrogen receptor (ER) expression status. This ESC8 molecule apparently is nontoxic to normal breast epithelial cells, as well as to other non-cancer cells. ESC8 induces apoptosis through an intrinsic pathway in ER-negative MDA-MB-231 cells. In addition, ESC8-treatment induces autophagy in these cells by interfering with the mTOR activity. This is the first example of an estrogen structure-based molecule that co-induces apoptosis and autophagy in breast cancer cells. Further in vivo study confirms the role of this molecule in tumor regression. Together, our results open new perspective of breast cancer chemotherapy through a single agent, which could provide the therapeutic benefit across all stages of breast cancer.

Development of new estradiol-cationic lipid hybrids: Ten-carbon twin chain cationic lipid is a more suitable partner for estradiol to elicit better anticancer activity

“…Inclusion of ES to other cationic lipids (C8, C12) induces selectivity but offers limited anticancer effect in broad range of cancer cells. We believe, 5c targeted and modulated the ER and/or its existing pathways unfavorably and selectively in ER ± breast cancer cells (and also in ER þ non-breast cancer cells), as like ES-C8 (here, 5b) did in ER ± breast cancer cells through induction of apoptosis and autophagy [18].…”

“…Previously we found that ES-C8 was the most potent anticancer molecule known among this class of molecules [18]. Here, ES-C10 (5c) exhibited 5e12 folds lesser IC 50 than IC 50 exhibited by ES-C8 (5b) in different cancer cells.…”

“…The distinctive novel structural features common to the cationic estradiol derivatives 5aee disclosed in the present investigation include: (a) The presence of hydrophobic groups which are directly linked to the positively charged nitrogen atom and (b) the presence of ER-binding 17b-estradiol group. The details of the synthetic procedures for the cationic estradiol conjugates 5aee, as per our previous report [18], are shown in Scheme 2 and are described in the experimental section. More specifically, 3-hydroxyl group of estrone was protected as tertiary butyl dimethyl silyl ether, alkylation at C-17-keto group of protected estrone using ally bromide and Mg yielded the 17-a allyl derivative of estrone.…”

“…This rationalise, among other possibilities, generation of cationic lipidbased anticancer hybrids. Recently we have reported different classes of cationic lipidated small molecules (Scheme 1a)) that include cationic lipid conjugates of estradiol [18], haloperidol [19] and benzamides [20]. Others have utilized this hybridization concept towards developingemodin-based anticancer agents [21].…”

“…The optimization was done among three molecules, starting from two (ES-C2), eight (ES-C8) and sixteen (ES-C16) carbon chain lengths. Among the three compounds, ES-C8 was found to exhibit potent anti-breast cancer activity [18]. Since ES-C8 is an estradiol-associated molecule we expected that like other estrogen-based drugs (Scheme 1b) this molecule would exhibit usual anti-breast cancer activity against only ER-positive cancers [22e24].…”