Targeting IL8 as a sequential therapy strategy to overcome chemotherapy resistance in advanced gastric cancer

Abstract

Systemic chemotherapy with multiple drug regimens is the main therapy option for advanced gastric cancer (GC) patients. However, many patients develop relapse soon. Here, we evaluated the therapeutic potential of targeting interleukin-8 (IL8) to overcome resistance to chemotherapy in advanced GC. RNA sequencing revealed crucial molecular changes after chemotherapy resistance, in which the expression of IL8 was significantly activated with the increase in drug resistance. Subsequently, the clinical significance of IL8 expression was determined in GC population specimens. IL8-targeted by RNA interference or reparixin reversed chemotherapy resistance with limited toxicity in vivo and vitro experiments. Sequential treatment with first-line, second-line chemotherapy and reparixin inhibited GC growth, reduced toxicity and prolonged survival. Collectively, our study provides a therapeutic strategy that targeting IL8 as a sequential therapy after chemotherapy resistance in advanced GC.

Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications

“…Studies have shown that CSCs function as a major driving force of drug-resistance and they are deeply involved in the pathogenesis of drug resistance ( 192 , 193 ). Targeting cytokine/receptor signals holds promise for overcoming drug resistance and restoring sensitivity to anticancer therapies ( 77 , 194 ). For example, IL-4 has been reported to protect CRC CSCs from apoptosis and the potential benefits of standard chemotherapies, radiotherapies or immunotherapies in combination with IL-4 inhibitors may enhance the therapeutic efficacy in the context of CRC ( 77 ).…”

“…A study by Jiang et al. ( 194 ) assessed the efficacy of targeting IL.-8 signaling to overcome drug resistance in advanced gastric cancer, and their results showed that increased expression of IL8 significantly activated drug resistance. IL8 signaling targeted by RNA interference or reparixin reversed chemotherapy resistance with limited toxicity in vivo and in vitro .…”

Role of Interleukins and New Perspectives in Mechanisms of Resistance to Chemotherapy in Gastric Cancer

“…In vivo and in vitro experiments showed that IL8-targeted by RNA interference or reparixin reversed chemotherapy resistance with limited toxicity. Consequently, it was shown that the sequential treatment with first and second-line chemotherapy followed by reparixin inhibited the growth of GC and reduced the toxicity of the treatment and prolonged survival of mice [ 32 ] ( Table 1 ). Some limitations exist in this study, including no exploration of the biology of the IL-8 system in myeloid leukocyte populations present in immunodeficient mice, and IL-8 absence from the rodent genome [ 32 ] ( Table 1 ).…”

“…Consequently, it was shown that the sequential treatment with first and second-line chemotherapy followed by reparixin inhibited the growth of GC and reduced the toxicity of the treatment and prolonged survival of mice [ 32 ] ( Table 1 ). Some limitations exist in this study, including no exploration of the biology of the IL-8 system in myeloid leukocyte populations present in immunodeficient mice, and IL-8 absence from the rodent genome [ 32 ] ( Table 1 ). The above data suggest that the assessment of IL-8 levels in GC patients may be useful as a predictive biomarker in monitoring drug resistance in these patients.…”

Adenosine signaling: Optimal target for gastric cancer immunotherapy

“…However, increasing numbers of studies have shown that surgery cannot benefit patients with unresectable AGC and post-operative complication is a negative predictor of long-term survival outcomes for them (9). Systemic chemotherapy with multiple drug regimens is the main therapy choice to further prolong the survival of post-or non-operative AGC patients (10). Despite relevant progress, the impact of chemotherapy on AGC patients' survival is still unsatisfactory, especially patients with multiple distant metastases (1).…”