Counteracting Cisplatin-Induced Testicular Damages by Natural Polyphenol Constituent Honokiol

Abstract

Cisplatin, despite its anti-cancer ability, exhibits severe testicular toxicities when applied systemically. Due to its wide application in cancer treatment, reduction of its damages to normal tissue is an imminent clinical need. Here we evaluated the effects of honokiol, a natural lipophilic polyphenol compound, on cisplatin-induced testicular injury. We showed in-vitro and in-vivo that nanosome-encapsulated honokiol attenuated cisplatin-induced DNA oxidative stress by suppressing intracellular reactive oxygen species production and elevating gene expressions of mitochondrial antioxidation enzymes. Nanosome honokiol also mitigated endoplasmic reticulum stress through down regulation of Bip-ATF4-CHOP signaling pathway. Additionally, this natural polyphenol compound diminished cisplatin-induced DNA breaks and cellular apoptosis. The reduced type I collagen accumulation in the testis likely attributed from inhibition of TGFβ1, αSMA and ER protein TXNDC5 protein expression. The combinatorial beneficial effects better preserve spermatogenic layers and facilitate repopulation of sperm cells. Our study renders opportunity for re-introducing cisplatin to systemic anti-cancer therapy with reduced testicular toxicity and restored fertility.

The protective effect of crocin on cisplatin-induced testicular impairment in rats

“…Several studies found that CIS causes severe testicular damage through impairment of Leydig cell function (inhibiting testosterone production) and induction of germ cell apoptosis. Besides the DNA damage, excessive production of reactive oxygen species (ROS) is also implicated as one of the main causes of CIS-induced testicular damage [ 9 ].…”

Prevention of Testicular Damage by Indole Derivative MMINA via Upregulated StAR and CatSper Channels with Coincident Suppression of Oxidative Stress and Inflammation: In Silico and In Vivo Validation

“…Afsar et al methods were used to assess SOD and GPx activity [ 39 , 40 ]. The total antioxidant capacity of testicular tissues was analyzed by OxiSelect Total Antioxidant Capacity Assay (TAC assay, Cell Biolabs, Inc., San Diego, CA, USA) [ 17 ].…”

“…CDDP can induce Leydig cell dysfunction and testicular steroidogenic synthesis disorders in animals, inhibiting testosterone production and causing infertility [ 15 ]. Furthermore, CDDP decreases sperm motility and activation [ 16 , 17 ]. CatSper is a voltage-gated calcium channel that is expressed in sperm, and it leads to hyperactivated motility and fertility in males.…”

Grape seed proanthocyanidin extract ameliorates cisplatin‐induced testicular apoptosis via PI3K/Akt/mTOR and endoplasmic reticulum stress pathways in rats

“…Cisplatin (CIS) is an effective chemotherapy drug for the treatment of testicular cancer, gynecologic cancer, gastrointestinal cancer, and malignant diseases (Albany et al., 2021). However, there are numerous side‐effects during CIS treatment (Azarbarz et al., 2020), especially testicular toxicity (Wang, Lai, et al, 2020). Exposure to CIS led to testicular atrophy and decrease in the number, viability, and motility of sperm, resulting in spermatogenesis inhibition and infertility (Fouad et al., 2017).…”