Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels

Abstract

Resistance to oxaliplatin (L-OHP) is a major obstacle to successful chemotherapy in colorectal cancer (CRC). In the present study, the ability of gambogic acid (GA) to reverse L-OHP resistance in CRC LoVo cells was investigated. L-OHP-resistant LoVo/L-OHP cells were established by exposing them to increasing concentrations of L-OHP. GA-reversed L-OHP-sensitive LoVo/L-OHP/GA cells were established by exposure to 0.5 µmol/l GA for 2 weeks. A Cell Counting Kit-8 assay was used to assess levels of proliferation. Flow cytometry was applied to detect apoptosis rates. Transwell assays were used to analyse invasion. Inductively coupled plasma mass spectrometry was used to determine intracellular platinum (Pt) content. Western blot analysis was used to reveal the protein levels of Human copper transporter 1 (hCTR1), Copper-transporting p-type adenosine triphosphatases 1 (ATP7A) and Copper-transporting p-type adenosine triphosphatases 2 (ATP7B). LoVo/L-OHP and LoVo/L-OHP/GA cell lines were successfully established, and it was identified that L-OHP inhibited the proliferation of LoVo, LoVo/L-OHP and LoVo/L-OHP/GA cells in a dose-dependent manner. Compared with the parent LoVo cells, the anti-apoptosis and invasion properties of LoVo/L-OHP cells were enhanced, and were reversed by GA treatment. Intracellular Pt content was highest in the LoVo cells, followed by LoVo/L-OHP/GA cells, and then lowest in the LoVo/L-OHP cells. Downregulated hCTP1 and upregulated ATP7A and ATP7B were associated with L-OHP resistance, and GA reversed the resistance by increasing levels of hCTR1 and decreasing levels of ATP7A and ATP7B. In conclusion, GA has the potential ability to reverse L-OHP resistance in CRC cells by increasing intracellular Pt content, which it achieves by increasing hCTR1 levels and decreasing ATP7A and ATP7B levels. GA may represent a promising treatment agent for L-OHP resistance.

Inhibition of miR‑96 enhances the sensitivity of colorectal cancer cells to oxaliplatin by targeting TPM1

“…Considering the potential of miRNA in the chemotherapy of cancers, the present study focused on the effects of downregulation of miR-96 on the sensitivity of CRC cells to oxaliplatin. Oxaliplatin, as a first-line anticancer agent, is a preferential therapeutic for CRC (3). In the present study, oxaliplatin suppressed the viability and promoted the apoptosis of CRC cells.…”

“…Although advances have been made in the treatment of CRC in recent years (20), multidrug resistance remains the major obstacle of chemotherapy (3). Aberrant expression of certain miRNAs has crucial roles in the development of chemoresistance (21).…”

“…Oxaliplatin, as a first-line anticancer agent, is a preferential therapeutic for CRC ( 3 ). In the present study, oxaliplatin suppressed the viability and promoted the apoptosis of CRC cells.…”

“…Colorectal cancer (CRC) is one of the most common malignancies worldwide (1,2). The routine therapeutic strategy for CRC is surgery combined with platinum-based treatment (3,4). Oxaliplatin, as a platinum-based drug, inhibits the progression of CRC by binding to and cross-linking the DNA of cancer cells (3).…”

“…The routine therapeutic strategy for CRC is surgery combined with platinum-based treatment (3,4). Oxaliplatin, as a platinum-based drug, inhibits the progression of CRC by binding to and cross-linking the DNA of cancer cells (3). Although advances have been made in the treatment of CRC, the overall survival rate of CRC patients remains unsatisfactory due to chemoresistance and recurrence (5,6).…”