Construction of SLC16A1/3 Targeted Gallic Acid-Iron-Embelin Nanoparticles for Regulating Glycolysis and Redox Pathways in Cervical Cancer

  • Mol Pharm. 2023 Jun 12. doi: 10.1021/acs.molpharmaceut.3c00294.
Shiwan You  1 ,  Jing Zhang  1  2 ,  Lan Yu  3 ,  Zuoping Li  1  4 ,  Jiaru Zhang  1 ,  Na Zhao  1 ,  Zhenzhen Xie  1  4 ,  Youping Li  1 ,  Zubair Akram  4 ,  Shiguo Sun  1  5
Affiliations
  • 1. Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Shihezi University College of Pharmacy, Shihezi 832003, Xinjiang, China.
  • 2. School of Medicine, Xinjiang University of Science & Technology, Korla, 841000, China.
  • 3. Shanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest Agriculture and Forestry University, Yangling, Shaanxi 712100, China.
  • 4. Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Shihezi University College of Chemistry and Chemical Engineering, Shihezi 832002, Xinjiang, China.
  • 5. College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China.
PMID: 37307591 DOI: 10.1021/acs.molpharmaceut.3c00294
Abstract

SLC16A1 and SLC16A3 (SLC16A1/3) are highly expressed in cervical cancers and associated with the malignant biological behavior of Cancer. SLC16A1/3 is the critical hub for regulating the internal and external environment, glycolysis, and redox homeostasis in cervical Cancer cells. Inhibiting SLC16A1/3 provides a new thought to eliminate cervical Cancer effectively. There are few reports on effective treatment strategies to eliminate cervical Cancer by simultaneously targeting SLC16A1/3. GEO database analysis and quantitative reverse transcription polymerase chain reaction experiment were used to confirm the high expression of SLC16A1/3. The potential inhibitor of SLC16A1/3 was screened from Siwu Decoction by using network pharmacology and molecular docking technology. The mRNA levels and protein levels of SLC16A1/3 in SiHa and HeLa cells treated by Embelin (EMB) were clarified, respectively. Furthermore, the Gallic acid-iron (GA-Fe) drug delivery system was used to improve its anti-cancer performance. Compared with normal cervical cells, SLC16A1/3 mRNA was over-expressed in SiHa and HeLa cells. Through the analysis of Siwu Decoction, a simultaneously targeted SLC16A1/3 inhibitor EMB was discovered. It was found for the first time that EMB promoted lactic acid accumulation and further induced redox dyshomeostasis and glycolysis disorder by simultaneously inhibiting SLC16A1/3. The gallic acid-iron-Embelin (GA-Fe@EMB) drug delivery system delivered EMB, which had a synergistic anti-cervical Cancer effect. Under the irradiation of a near-infrared laser, the GA-Fe@EMB could elevate the temperature of the tumor area effectively. Subsequently, EMB was released and mediated the lactic acid accumulation and the GA-Fe nanoparticle synergistic Fenton reaction to promote ROS accumulation, thereby increasing the lethality of the nanoparticles on cervical Cancer cells. GA-Fe@EMB can target cervical Cancer marker SLC16A1/3 to regulate glycolysis and redox pathways, synergistically with photothermal therapy, which provides a new avenue for the synergistic treatment of malignant cervical Cancer.

Keywords
GA-Fe@EMB; SLC16A1 and SLC16A3; cervical cancer; glycolysis; oxidative stress; synergistic therapy.
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