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Background/aims <p>Gastric cancer (GC) is a significant global health issue with high incidence rates and poor prognoses, ranking among the top prevalent cancers worldwide. Due to undesirable side effects and drug resistance, there is a pressing need for the development of novel therapeutic strategies. Understanding the interconnectedness of the <i>JAK2</i>/<i>STAT3</i>/<i>mTOR</i>/<i>PI3K</i> pathway in tumorigenesis and the role of Astaxanthin (ASX), a red ketocarotenoid member of xanthophylls and potent antioxidant and anti-tumor activity, can be effective for cancer treatments. This study aimed to investigate the effect of ASX-loaded nanoparticles on the survival of MKN-45 GC cells and the expression of <i>JAK2</i>/<i>STAT3</i>/<i>mTOR</i>/<i>PI3K</i>, offering insights into potential targeted therapies for GC.</p> Methods <p>The growth status and survival rate of MKN-45 GC cell lines were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT) assay, and the optimal IC50 concentration of ASX, PLGA, and ASX + PLGA was estimated. Also, the clonogenic assay was performed to determine the reproductive power and colony formation of under-treatment cells. Apoptosis and necroptosis of cells were evaluated using acridine orange (AO) staining. The western blot assessed the protein’s level of expression and intensity (<i>JAK2/STAT3/mTOR/PI3K</i>). SPSS version 16 software was used for statistical analysis, P-value was considered lower than 0.05.</p> Results <p>Based on the results, increasing concentrations of ASX and ASX + PLGA led to a decrease in the viability of MKN-45 cells compared to the control group (<i>P</i> &lt; 0.001). This value was lower for cells treated with ASX + PLGA (<i>P</i> = 0.003). The IC50 values for each of the studied groups (ASX, ASX + PLGA, and PLGA) were 81.45&#xa0;µg/ml, 51.45&#xa0;µg/ml, and 3.383&#xa0;mg/ml, respectively. The levels of expression and intensity of <i>JAK2</i>, <i>STAT3</i>, and <i>mTOR</i> proteins in the Western blotting analysis under ASX + PLGA treatment increased compared to the control group. Conversely, the levels of expression and intensity of <i>P-JAK2</i>, <i>P-STAT3</i>, and <i>P-mTOR</i> proteins in the ASX + PLGA treatment group decreased by 41%, 34%, 37%, and 43%, respectively, compared to the control group. Protein expression levels and intensities of <i>JAK2</i>, <i>STAT3</i>, and <i>mTOR</i> significantly increased when treated with PLGA, ASX, and ASX + PLGA compared to the control group (<i>P</i> &lt; 0.001).</p> Conclusions <p>The encapsulation of ASX in PLGA nanoparticles enhances drug stability, enables targeted delivery, and allows for sustained release. This study highlights the therapeutic potential of ASX-loaded nanoparticles in targeting <i>JAK2/STAT3/mTOR/PI3K</i> pathways in GC treatment. Further research is needed to understand the mechanisms and clinical applications of this novel immunotherapy strategy.</p>

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Astaxanthin-loaded PLGA nanoparticles inhibit survival of MKN-45 gastric cancer cell line by modulating JAK2/STAT3/mTOR/PI3K pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月9日

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  • Mohammad Hossein YektaKooshali,
  • Mahdieh SobhZahedi,
  • Seyed Mohammad Taghi Razavi Tousi,
  • Masoud Hamidi,
  • Leila Modiri

摘要

Background/aims

Gastric cancer (GC) is a significant global health issue with high incidence rates and poor prognoses, ranking among the top prevalent cancers worldwide. Due to undesirable side effects and drug resistance, there is a pressing need for the development of novel therapeutic strategies. Understanding the interconnectedness of the JAK2/STAT3/mTOR/PI3K pathway in tumorigenesis and the role of Astaxanthin (ASX), a red ketocarotenoid member of xanthophylls and potent antioxidant and anti-tumor activity, can be effective for cancer treatments. This study aimed to investigate the effect of ASX-loaded nanoparticles on the survival of MKN-45 GC cells and the expression of JAK2/STAT3/mTOR/PI3K, offering insights into potential targeted therapies for GC.

Methods

The growth status and survival rate of MKN-45 GC cell lines were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT) assay, and the optimal IC50 concentration of ASX, PLGA, and ASX + PLGA was estimated. Also, the clonogenic assay was performed to determine the reproductive power and colony formation of under-treatment cells. Apoptosis and necroptosis of cells were evaluated using acridine orange (AO) staining. The western blot assessed the protein’s level of expression and intensity (JAK2/STAT3/mTOR/PI3K). SPSS version 16 software was used for statistical analysis, P-value was considered lower than 0.05.

Results

Based on the results, increasing concentrations of ASX and ASX + PLGA led to a decrease in the viability of MKN-45 cells compared to the control group (P < 0.001). This value was lower for cells treated with ASX + PLGA (P = 0.003). The IC50 values for each of the studied groups (ASX, ASX + PLGA, and PLGA) were 81.45 µg/ml, 51.45 µg/ml, and 3.383 mg/ml, respectively. The levels of expression and intensity of JAK2, STAT3, and mTOR proteins in the Western blotting analysis under ASX + PLGA treatment increased compared to the control group. Conversely, the levels of expression and intensity of P-JAK2, P-STAT3, and P-mTOR proteins in the ASX + PLGA treatment group decreased by 41%, 34%, 37%, and 43%, respectively, compared to the control group. Protein expression levels and intensities of JAK2, STAT3, and mTOR significantly increased when treated with PLGA, ASX, and ASX + PLGA compared to the control group (P < 0.001).

Conclusions

The encapsulation of ASX in PLGA nanoparticles enhances drug stability, enables targeted delivery, and allows for sustained release. This study highlights the therapeutic potential of ASX-loaded nanoparticles in targeting JAK2/STAT3/mTOR/PI3K pathways in GC treatment. Further research is needed to understand the mechanisms and clinical applications of this novel immunotherapy strategy.