The Effects of 4′-Esterified Resveratrol Derivatives on Calcium Dynamics in Breast Cancer Cells

Abstract

Triple-negative breast cancer is a highly aggressive subtype of breast cancer. Frequently, breast cancer cells modulate their calcium signaling pathways to optimize growth. Unique calcium pathways in breast cancer cells could serve as a way to target tumorigenic cells without affecting normal tissue. Resveratrol has previously been shown to activate calcium signaling pathways. We use cell viability, single-cell calcium microscopy, and RT-PCR assays to determine the activity and mechanism of three different 4′-esterified resveratrol derivatives. We demonstrate that two of the derivatives reduce cell viability more effectively than resveratrol in MDA-MB-231 human breast cancer cells. The derivatives also activate similar pro-apoptotic calcium signaling pathways. In particular, the pivalated and butyrated resveratrol derivatives are intriguing putative chemotherapeutics because they are more effective at decreasing cell viability in vitro and inhibiting the plasma membrane Ca2+-ATPase, a protein that is often modulated in breast cancer.

Resveratrol derivatives increase cytosolic calcium by inhibiting plasma membrane ATPase and inducing calcium release from the endoplasmic reticulum in prostate cancer cells

“…Modifications to RES may help increase efficacy of RES as a chemotherapeutic by increasing the activity on pathways specific to chemotherapeutic activity and identify structural components that are important for RES chemotherapeutic activity. Previous studies have demonstrated that modifying the 4′ hydroxyl group on resveratrol increased its chemotherapeutic activity [28]. Here we have esterified the 4’ hydroxyl with a butyrate (BuRV), isobutyrate (IsoRV), and pivalate (PIV) group (Fig.…”

“…Cell viability was determined using an MTT assay as described previously [28]. Briefly, PC-3 cells were plated at 10,000 cells per well in a Greiner Bio-One Cellstar 96-well plate (Greiner Bio-One, Monroe, NC, USA).…”

“…Fura-2 loading and experimental protocols performed were similar to those performed as described previously [28]. Briefly, cells were plated and grown in an 8-well chamber, washed twice with 1:1 PBS:FBS solution, and incubated at 37 °C in 5% CO 2 for 30 min in 3 μM Fura-2 in Ringer's solution (NaCl 150 mM, glucose 10 mM, HEPES 5 mM, KCl 5 mM, MgCl2 1 mM, CaCl2 2 mM, pH 7.4).…”

“…RES activates a large and sustained calcium signal in tumor cells that results in tumor cell death [23,25]. One of the advantages of RES promiscuity is that it can both activate IP 3 R and inhibit PMCA leading to a cytotoxic increase in [Ca 2+ ] i [[26], [27], [28]]. In this study we are screening for RES derivatives that are more potent than their parent compound at increasing cytoplasmic calcium by inhibiting PMCA and stimulating IP 3 R.…”

Estrogenic, Antiestrogenic and Antiproliferative Activities of Euphorbia bicolor (Euphorbiaceae) Latex Extracts and Its Phytochemicals

“…Another study showed that rutin acted as a chemosensitizer by increasing the cytotoxicity of two chemotherapeutic drugs, cyclophosphamide and methotrexate, in MDA-MB-231 cancer cells [58]. The role of calcium in the proliferation and invasion of cancer cells, as well as the increased expression of calcium channels in some cancers, led to the assessment of calcium channel inhibitors as potential therapy for cancer [61,62]. It is important to find new chemotherapeutics with unique effective mechanisms of action for treating cancers.…”