Sufentanil attenuates oxaliplatin cytotoxicity via inhibiting connexin 43-composed gap junction function

Abstract

Comprehensive strategies for the treatment of colorectal cancer (CRC) have become increasingly important. One of the most important factors is pain relief. Therefore, patients with CRC are concurrently treated with analgesics and chemotherapeutic agents; however, the effects of analgesics on the therapeutic activity of chemotherapeutic agents remain largely unknown. The present study investigated the effects of three widely used analgesics in clinics: Fentanyl, remifentanil and sufentanil, on the cytotoxicity of oxaliplatin, a commonly used chemotherapeutic agent for CRC. Furthermore, the underlying mechanisms of those effects in association with connexin 43 (Cx43)‑composed gap junction (GJ) function were analyzed. The Lovo, Colo320, HCT116 and HT29 human CRC cell lines, with or without Cx43 expression, were used to examine the effects of the three analgesics on the cytotoxicity of oxaliplatin. The results demonstrated that in the cell lines expressing Cx43 (Lovo and Colo320), the cytotoxicity of oxaliplatin was attenuated and Cx43 GJ function was inhibited. Sufentanil, not fentanyl or remifentanil, inhibited Cx43 GJ function effectively, and reduced the cytotoxicity of oxaliplatin. In contrast, these effects were not observed in the other two colon cancer cell lines not expressing Cx43 (HCT116 and HT29). These results suggested that alternation of Cx43 GJ function may regulate the cytotoxicity of oxaliplatin in regard to CRC. Furthermore, sufentanil, not fentanyl or remifentanil, suppressed the cytotoxicity of oxaliplatin through inhibition of Cx43 GJ function. These results may be beneficial for the treatment of CRC and reduction of treatment resistance.

CX43 down-regulation promotes cell aggressiveness and 5-fluorouracil-resistance by attenuating cell stiffness in colorectal carcinoma

“…The overexpressing CX43 in glioblastoma cells could elevate significant permeability to paclitaxel and doxorubicin 46 . Similarly, in CRC, CX43 can sensitize CRC cells to paclitaxel 47 , oxaliplatin 49 , and 5-FU 16 by enhancing the bystander effect. Indeed, we identified that CX43 overexpressing enhanced GJIC in CRC cells, thereby increasing CRC cell sensitivity to 5-FU and cisplatin, and that Oleamide, a gap junction inhibitor, could restore chemosensitivity by reducing CRC cell death.…”

A New Side-effect of Sufentanil: Increased Monocyte-endothelial Adhesion

“…Compared to the other two opioids, sufentanil is the agonist with the highest a nity toward µ-opioid receptors. This may explain why sufentanil can interact with µ-opioid receptors and activate the downstream signalling pathways of G proteins, but fentanyl and remifentanil cannot [30,31]. This might also be the reason why sufentanil could alter Cx43 channel function, while fentanyl and remifentanil did not have this kind of effect.…”

By regulating miR-182-5p/<i>BCL10</i>/<i>CYCS</i>, sufentanil reduces the apoptosis of umbilical cord mesenchymal stem cells caused by ropivacaine

“…In the tumor microenvironment, sufentanil attenuates cytotoxicity by inhibiting connexin 43-composed gap junction function in the treatment of colorectal cancer (20). Ropivacaine reversibly reduced the permeability of the nerve fiber membrane to sodium ions, it slowed the speed of depolarization, and it alleviated stress (21). Peroxides, DNA damage, and calcium homeostasis may induce neuron apoptosis, and mitochondrial dysfunction may activate metabolic changes related to apoptosis (22).…”