17‐allylamino‐17‐demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species‐induced cell death

Abstract

Hyperthermia enhances the anticancer effects of thymidylate synthase (TYMS) inhibitors (raltitrexed, RTX) and improves the precise biochemical mechanisms partially through enhancement of intracellular drug absorption. Recent research focuses on the potential anticancer drug target Heat Shock Protein 90 (HSP90), which could increase the sensitivity of cancer cells to TYMS inhibitors; however, with different HSP90 inhibitors, several research studies finally showed a poor efficacy in preclinical or clinical research. Here, we showed that 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG, HSP90 inhibitor) affects the efficacy of chemotherapy through antioxidant activation–induced resistance. In this study, we found that RTX, alone or in combination with hyperthermia, triggers reactive oxygen species (ROS) exposure and thus induces cell death. Also, the addition of hyperthermia showed more ROS exposure and function. The pharmacologic inhibition of HSP90 reversed the effects of chemotherapeutical treatments, while the overexpression of HSP90 showed no relation with these effects, which demonstrated that dysregulation of HSP90 might have a significant impact on chemotherapeutic treatments. The addition of 17‐AAG increased the activation of antioxidant with increased antioxidant enzymes, thus affecting the RTX efficacy.

Heat shock protein 90α inhibitor, PU-H71 in combination with DHEA promoting apoptosis in triple-negative breast cancer cell line MDA-MB-231

“…Moreover, the significant decrease in the ROS level in MDA-MB-231 cells treated with PU-H71 alone (Fig. 3) could be explained in analogy to a previous study that showed that Hsp90 inhibitors 17-AAG and 17-DMAG attenuated the oxidative stress via induction of some antioxidant enzymes such as manganese superoxide dismutase, glutathione peroxidase and catalase, which decrease the ROS level (Li et al, 2018). In addition, the NADPH oxidases (Nox), a family of seven enzymes, are the major source of ROS that consume NADPH to produce superoxide (Chen et al, 2011).…”

Hyperthermic intraperitoneal chemotherapy with recombinant mutant human TNF-α and raltitrexed in mice with colorectal-peritoneal carcinomatosis

“…After inoculation, animals were randomly assigned to six mice each group for different treatments for 30 min according to our previous study. 11,29 The difference between IPEC and HIPEC was the temperature of perfusate. The temperature of IPEC was 37°C, and that of HIPEC was 42°C.…”

“…The dose of rmhTNF was referred to previous literatures, 20 and that of RTX was chosen from our previous study. 11,29 The remaining identical perfusion process was performed as previously reported. 11,29…”

“…27,28 Our previous studies confirmed that HIPEC with RTX was a therapeutic strategy to treat CRC-PC in mouse models without any severe untoward effects accompanied. 11,29 Besides, compared to the systemic chemotherapy with the intravenous drip of RTX, HIPEC could promote the intracellular absorption of RTX according to pharmacokinetic studies. 11…”

Raltitrexed regulates proliferation and apoptosis of HGC-27 cells by upregulating RSK4

“…The most common adverse events associated with raltitrexed are neutropenia, diarrhea, and elevated liver enzymes [8]. Compared with 5-FU, raltitrexed has better hematological and gastrointestinal tolerability, and because it does not cause accumulation of related metabolites, it exhibits reduced cardiotoxicity in patients [5,9]. Raltitrexed is associated with a significantly lower incidence of severe leukopenia and mucositis compared with 5FU plus leucovorin [9].…”