Innovative challenge for the inhibition of hepatocellular carcinoma progression by combined targeting of HSP90 and STAT3/HIF-1α signaling

被引：21

作者：

Saber, Sameh ^{[1
]}

Abd El-Fattah, Eslam E. ^{[2
]}

Abdelhamid, Amir Mohamed ^{[1
]}

Mourad, Ahmed A. E. ^{[3
]}

Hamouda, Manal Ali Mahrous ^{[4
]}

Elrabat, Amr ^{[5
]}

Zakaria, Sahar ^{[6
]}

Haleem, Amira A. ^{[7
]}

Mohamed, Sherin Z. ^{[8
]}

Elgharabawy, Rehab Mohamed ^{[9
]}

Morsy, Nesreen Elsayed ^{[10
]}

Khalaf, Noura El Adle ^{[11
]}

Mohammed, Osama A. ^{[12
]}

El-Bahouty, Waleed Barakat ^{[13
]}

Mostafa, Sally Abdallah ^{[7
]}

Abdelhady, Rasha ^{[14
]}

Galal, Omneya ^{[15
]}

ElSaid, Zeinab H. ^{[16
]}

Yahya, Galal ^{[17
]}

Shata, Ahmed ^{[11
,18
]}

Youssef, Mahmoud E. ^{[1
]}

机构：

[1] Delta Univ Sci & Technol, Fac Pharm, Dept Pharmacol, Gamasa 11152, Egypt

[2] Delta Univ Sci & Technol, Fac Pharm, Dept Biochem, Gamasa 11152, Egypt

[3] Port Said Univ, Fac Pharm, Pharmacol & Toxicol Dept, Port Said 42511, Egypt

[4] Menoufia Univ, Clin Pharm Dept, Fac Pharm, Menoufia 32511, Egypt

[5] Mansoura Univ, Fac Med, Gastroenterol & Hepatol Dept, Mansoura 35516, Egypt

[6] Mansoura Univ, Fac Med, Dept Trop Med, Mansoura 35516, Egypt

[7] Mansoura Univ, Fac Med, Med Biochem & Mol Biol Dept, Mansoura 35516, Egypt

[8] Horus Univ, Fac Med, Dept Internal Med, New Damietta 34518, Egypt

[9] Tanta Univ, Fac Pharm, Pharmacol & Toxicol Dept, Tanta 31527, Egypt

[10] Mansoura Univ, Mansoura Univ Sleep Ctr, Fac Med, Pulm Med Dept, Mansoura 35516, Egypt

[11] Mansoura Univ, Fac Med, Dept Clin Pharmacol, Mansoura 35516, Egypt

[12] Ain Shams Univ, Fac Med, Dept Clin Pharmacol, Cairo 11566, Egypt

[13] Tanta Univ, Fac Med, Pharmacol Dept, Tanta 31527, Egypt

[14] Fayoum Univ, Fac Pharm, Pharmacol & Toxicol Dept, Al Fayyum, Egypt

[15] Ahram Canadian Univ, Fac Pharm, Dept Pharmacol, Giza 12451, Egypt

[16] Mansoura Univ, Fac Med, Dept Med Physiol, Mansoura 35516, Egypt

[17] Zagazig Univ, Fac Pharm, Dept Microbiol & Immunol, Al Sharqia 44519, Egypt

[18] Delta Univ Sci & Technol, Fac Pharm, Dept Clin Pharm, Gamasa 11152, Egypt

来源：

BIOMEDICINE & PHARMACOTHERAPY | 2023年 / 158卷

关键词：

Hepatocellular carcinoma; Nifuroxazide; 17-DMAG; HSP90; STAT3; HIF-1; LIVER NEOPLASTIC CHANGES; OXIDATIVE STRESS; 17-DMAG; STAT3; HIF-1-ALPHA; EXPRESSION; HYPOXIA; RATS; ACTIVATION; PATHWAY;

D O I：

10.1016/j.biopha.2022.114196

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Hepatocellular carcinoma (HCC) is the third foremost cause of cancer-related deaths. HCC has a very bad prognosis because it is asymptomatic in the early stages, resulting in a late diagnosis, and it is highly resistant to conventional chemotherapy. Such chemotherapies have been proven disappointing because they provide extremely low survival benefits. This study discloses that the STAT3/HIF-1 alpha is an auspicious therapeutic attack site for conceivable repression of HCC development. A site that can be targeted by simultaneous administration of a STAT3 inhibitor in the context of HSP90 inhibition. 17-DMAG binds to HSP90 and constrains its function, resulting in the degradation of HSP90 client proteins HIF-1 alpha and STAT3. Hypoxia recruits STAT3/HIF-1 alpha complex within the VEGF promoter. Additionally, it was acknowledged that STAT3 is an essential mediator of VEGF transcription by direct binding to its promoter. Furthermore, it induces HIF-1 alpha stability and enhances its transcriptional activity. Herein, we revealed that the combination therapy using 17-DMAG and nifuroxazide, a STAT3 inhibitor, repressed the diethylnitrosamine-induced alterations in the structure of the liver. This effect was mediated via decreasing the levels of the HSP90 client proteins HIF-1 alpha and pSTAT3 resulting in the sup-pression of the STAT3/HIF-1 alpha complex transcriptional activity. To conclude, 17-DMAG/NFXZD combination therapy-induced disruption in the STAT3/HIF-1 alpha loop led to a potential antiangiogenic activity and showed apoptotic potential by inhibiting autophagy and inducing ROS/apoptosis signaling. Additionally, this combi-nation therapy exhibited promising survival prolongation in mice with HCC. Consequently, the use of 17-DMAG/ NFXZD renders an inspirational perspective in managing HCC. However, further investigations are compulsory.

引用

页数：14