Cytotoxic, chemosensitizing and radiosensitizing effects of curcumin based on thioredoxin system inhibition in breast cancer cells: 2D vs. 3D cell culture system

Abstract

Targeting the thioredoxin/thioredoxin reductase (Trx/TrxR) system is a promising strategy to overcome cancer resistance to conventional therapy. The present study investigated the effect of curcumin on the Trx/TrxR system either alone or in combination with chemotherapy, or radiotherapy in human MCF-7 breast cancer cells seeded in 2 and 3D culture systems. Cell viability, thioredoxin reductase 1 (TrxR1) activity, and the genetic expression of Trx, TrxR1, Bcl2 and BAX genes were studied. The findings showed that the mode of culture significantly affected the response of cancer cells to different treatment modalities, as well as their gene expression patterns. Curcumin treatment resulted in a reduction of breast cancer cell proliferation and induction of apoptosis, an effect that may be mediated by manipulating Trx system components, mainly Trx expression, and to a lesser extent TrxR1 expression and concentration. Furthermore, curcumin increased the sensitivity of breast cancer cells to chemotherapy and radiotherapy by reducing Trx and TrxR1 expression levels. Thus, curcumin may have a potential role as a dose-modifying agent that can be used either to sensitize resistant cells to therapy or to reduce the dose of these therapeutic agents.

Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer

“…Curcumin inhibited TrxR activity more prominently in 2D cell culture than in 3D spheroid model of MCF-7 cells when combined with radiation. However, cell viability was significantly reduced under both the culture settings [33] .…”

“…Se-D3 Reversible inhibition of TrxR 4–10 μg/ml Melanoma (A375) [37] 4. i. Curcumin Michael addition to TrxR and conversion into ROS generating enzyme 30–100 µM Breast (MCF7 2D monolayer and 3D spheroid) [33] 10 µM Squamous carcinoma (HeLa & FaDu) [40] 10 µM HNSCC (FaDu, JHU022, SQ20B) [10] Diet enriched with 1% w/v curcumin beginning on day 7 after tumor transplant (2Gy x 3) FaDu-CMV-Luciferase cells in to athymic nude mice ii. dimethoxy-curcumin 3.1 µM NSCLC (A549) [26] 5.…”

Tumor Organoid and Spheroid Models for Cervical Cancer

“…In this regard, 2D cell cultures have limited ability to mimic the TME in terms of cell morphology, gene expression at the RNA level, and intracellular signaling. Drug resistance between 2D cell cultures and cells in in vivo tumors may differ significantly in this regard [18][19][20].…”

3D Breast Tumor Models for Radiobiology Applications

“…Remaining studies have used reconstituted basement membrane-based substrates such as Matrigel where the cell-substrate interaction dominates the 3D cell attachment. Expectedly, 3D cultures show varying radiation responses when compared to the monolayer cultures [ 102 , 103 ]. With an upregulation of expression of stem cell-like markers, the 3D cultures have been shown to present increased resistance to radiation [ 103 , 104 ].…”