Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach

Osama A Mohammed; Mustafa Ahmed Abdel-Reheim; Lobna A Saleh; Mohannad Mohammad S Alamri; Jaber Alfaifi; Masoud I E Adam; Alshaimaa A Farrag; AbdulElah Al Jarallah AlQahtani; Waad Fuad BinAfif; Abdullah A Hashish; Sameh Abdel-Ghany; Elsayed A Elmorsy; Hend S El-Wakeel; Ahmed S Doghish; Rabab S Hamad; Sameh Saber

doi:10.3390/ph16081123

Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach

Pharmaceuticals (Basel). 2023 Aug 9;16(8):1123. doi: 10.3390/ph16081123.

Authors

Osama A Mohammed¹, Mustafa Ahmed Abdel-Reheim^{2

3}, Lobna A Saleh^{4

5}, Mohannad Mohammad S Alamri⁶, Jaber Alfaifi⁷, Masoud I E Adam⁸, Alshaimaa A Farrag^{9

10}, AbdulElah Al Jarallah AlQahtani¹¹, Waad Fuad BinAfif¹², Abdullah A Hashish^{13

14}, Sameh Abdel-Ghany¹⁵, Elsayed A Elmorsy^{15

16}, Hend S El-Wakeel^{17

18}, Ahmed S Doghish^{19

20}, Rabab S Hamad^{21

22}, Sameh Saber²³

Affiliations

¹ Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
² Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
⁴ Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
⁵ Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia.
⁶ Department of Family Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁷ Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁸ Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁹ Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
¹⁰ Unit of Anatomy, Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹¹ Department of Internal Medicine, Division of Dermatology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹² Department of Internal Medicine, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹³ Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
¹⁴ Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
¹⁵ Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
¹⁶ Pharmacology and Therapeutics Department, Qassim College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia.
¹⁷ Physiology Department, Benha Faculty of Medicine, Benha University, Benha 13518, Egypt.
¹⁸ Physiology Department, Albaha Faculty of Medicine, Albaha University, Al Baha 65799, Saudi Arabia.
¹⁹ Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo, Cairo 11829, Egypt.
²⁰ Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11231, Egypt.
²¹ Biological Sciences Department, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia.
²² Central Laboratory, Theodor Bilharz Research Institute, Giza 12411, Egypt.
²³ Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.

Abstract

Idiopathic pulmonary fibrosis (IPF) is an irreversible and life-threatening lung disease of unknown etiology presenting only a few treatment options. TGF-β signaling orchestrates a cascade of events driving pulmonary fibrosis (PF). Notably, recent research has affirmed the augmentation of TGF-β receptor (TβR) signaling via HSP90 activation. HSP90, a molecular chaperone, adeptly stabilizes and folds TβRs, thus intricately regulating TGF-β1 signaling. Our investigation illuminated the impact of alvespimycin, an HSP90 inhibitor, on TGF-β-mediated transcriptional responses by inducing destabilization of TβRs. This outcome stems from the explicit interaction of TβR subtypes I and II with HSP90, where they are clients of this cellular chaperone. It is worth noting that regulation of proteasome-dependent degradation of TβRs is a critical standpoint in the termination of TGF-β signal transduction. Oleuropein, the principal bioactive compound found in Olea europaea, is acknowledged for its role as a proteasome activator. In this study, our aim was to explore the efficacy of a combined therapy involving oleuropein and alvespimycin for the treatment of PF. We employed a PF rat model that was induced by intratracheal bleomycin infusion. The application of this dual therapy yielded a noteworthy impediment to the undesired activation of TGF-β/mothers against decapentaplegic homologs 2 and 3 (SMAD2/3) signaling. Consequently, this novel combination showcased improvements in both lung tissue structure and function while also effectively restraining key fibrosis markers such as PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. On a mechanistic level, our findings unveiled that the antifibrotic impact of this combination therapy likely stemmed from the enhanced degradation of both TβRI and TβRII. In conclusion, the utilization of proteasomal activators in conjunction with HSP90 inhibitors ushers in a promising frontier for the management of PF.

Keywords: HSP90/TGF-β; TβR; alvespimycin (17-DMAG); bleomycin-induced pulmonary fibrosis; oleuropein; proteasome.

Grants and funding

This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia (Grant No. GRANT3890).