RCCS Bioreactor-Based Modeled Microgravity Affects Gastric Cancer Cells and Improves the Chemotherapeutic Effect

Abstract

(1) Background: The main purpose of the study was to determine whether altered gravity might alter cell viability, improve drug delivery and modulate the expression of drug resistance-related genes. (2) Methods: This study investigated the intracellular mechanisms activated by microgravity in human resistant and sensitive gastric cancer cells (EPG85-257 RDB) and (EPG85-257 P). We used a rotary cell culture system (RCCS) developed by NASA to expose cells to altered gravity. The antitumor potential of microgravity was simulated by the RCCS bioreactor, and its effectiveness was evaluated in sensitive cell lines compared to chemotherapy-resistant cells concerning drug-sensitive cancer cells. Microgravity with chemotherapy was estimated by the viability assay, cytoskeleton imaging, MDR (multidrug resistance) gene expression analysis, MTCO-1 (mitochondrially encoded cytochrome C oxidase I), and 8-OHdG immunocytochemical analysis. (3) Results: We found that altered gravity combined with doxorubicin was cytotoxic to cancer cells. Cells following simulated microgravity revealed decreased expression of genes related to drug resistance and increased DNA/RNA damage marker expression. Cytoskeleton evaluation demonstrated significant reorganization of F-actin fibers after exposure to changed gravity conditions. (4) Conclusions: Intracellular alterations caused by simulated microgravity can increase gastric cancer cells’ sensitivity to chemotherapy. We have obtained satisfactory results showing the correlation between altered gravity and MDR phenomena which seems promising in future therapeutic applications.

Current Knowledge about the Impact of Microgravity on Gene Regulation

“… No change in AKT3 , PIK3CA , and NFE2L2. RPM, 72 h [ 196 ] A549 S-µ g induced increased expression of FCGBP , BPIFB , F5 , CST1 , and CFB Potential biomarkers for lung cancer 2D clinostat 24 h, 48 h, 72 h [ 197 ] Colorectal cancer DLD1 cells Upregulation of PTEN and FOXO3 Downregulation of AKT Increase in apoptosis RCCS-HARV [ 198 ] Gastric Cancer EPG85-257 RDB EPG85-257 P Reduced expression of genes related to drug resistance and increased DNA/RNA damage marker expression RCCS, 72 h [ 199 ] Liver cancer HepG2 cells hBTSCs Significant upregulation of OCT4 , SOX17 , and ALB in HepG2 cells RCCS, 15 d [ 200 ] Pancreas Cancer PaCa-44 Metabolic reprogramming orchestrated by the activation of HIF-1α and PI3K/Akt pathways RPM, 1 d, 7 d, 9 d ...…”

“…One recent publication ( Table 9 ) focused on changes in drug resistance of gastric cancer cells (GCC) cultured under s-µ g [ 199 ]. The human resistant and sensitive GCC (EPG85–257 RDB and EPG85–257 P) were exposed to an RCCS [ 199 ]. The authors showed that RCCS exposure, together with doxorubicin treatment, was cytotoxic to the GCC [ 199 ].…”

“…The human resistant and sensitive GCC (EPG85–257 RDB and EPG85–257 P) were exposed to an RCCS [ 199 ]. The authors showed that RCCS exposure, together with doxorubicin treatment, was cytotoxic to the GCC [ 199 ]. RCCS-exposed cells exhibited a reduced expression of genes related to drug resistance and increased DNA/RNA damage marker expression.…”

“…Simulated µ g conditions alter the expression of MDR genes in GGG, improve cell survival, and induce cytoskeletal changes to increase the susceptibility of GCC to chemotherapy. An interesting finding was that µ g weakened the action of genes associated with drug resistance [ 199 ].…”

3D tumor explant as a novel platform to investigate therapeutic pathways and predictive biomarkers in cancer patients

“…Of note, metabolomic analysis of supernatants of Erdheim-Chester disease (ECD) biopsies cultured for 4 days in RCCS Bioreactor revealed that the immunometabolic changes of trained immunity occurring in ECD lesions in vivo , such as increased glycolysis and accumulation of fumarate and malate, can be dampened by MAPK pathway inhibition ( 55 ). A recent study in gastric cancer showed that PDE culture in RCCS bioreactor recapitulates the action of chemotherapy in patients by affecting cell survival and by weakening the action of drug resistance-associated genes ( 56 ).…”