Adjudin - A Male Contraceptive with Anti-Cancer, Anti-Neuroinflammation and Anti-Ototoxicity Activities
- Pp. 29-45 (17)Yan-ho Cheng, Weiliang Xia, Xiang Xiao, Elizabeth Tang, Haiqi Chen, Qing Wen, Ying Gao, Dolores Mruk, Bruno Silvestrini and C. Yan Cheng
Adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, is an indazole-based compound and a testis-specific adherens junction disruption inducer. Adjudin is also an analog of the anticancer drug lonidamine. Studies have shown that adjudin is an effective male contraceptive in rats, rabbits, and beagle dogs. Adjudin is known to exert its effects primarily at the testis-specific actin-rich adherens junction known as ectoplasmic specialization (ES), most notably in the adluminal compartment called apical ES at the Sertoli-spermatid (step 8-19) interface in adult rat testes. Similar ultrastructures of apical ES are also found in the mouse, dog and human testes. Specifically, adjudin has been shown to perturb the organization of actin microfilament bundles at the ES, which in turn, perturbs adhesion protein complexes that utilize F-actin for attachment. The net result thus perturbs spermatid adhesion to the Sertoli cell in the testis, leading to massive exfoliation of elongated/elongating spermatids, to be followed by round spermatids, spermatocytes and differentiated spermatogonia, but not undifferentiated spermatogonia. This thus induces reversible infertility in rats, rabbits and beagle dogs due to the loss of germ cells in the seminiferous epithelium; and undifferentiated spermatogonia gradually replace all classes of germ cells via spermatogenesis, making the adjudin treated animals fertile again. Recent studies, however, have shown that adjudin also possesses biological activities to disrupt cancer growth and tumorigenesis. It also interferes with neuroinflammation by reducing ischemia-induced microglial activation in mice. Furthermore, adjudin protects rodent cochlear hair cells against gentamicin-induced ototoxicity via the SIRT3-ROS (SIRT3 also known as Sirtuin 3, silent mating type information regulation 3 homolog (a mitochondria NAD-dependent protein deacetylase)-reactive oxygen species) pathway. In this review, we summarize some of the recent findings, in particular the likely mechanism(s) of action, regarding the multiple biological activities of adjudin, illustrating this potential male contraceptive has other added health benefits, such as preventing cancer growth and development. Furthermore, its use as novel anti-cancer drug is an area of research that can be further explored. Using a multidrug nanocarrier to deliver adjudin, in combination with other anti-cancer drug(s) (e.g. doxorubicin), this approach has been used successfully to eradicate drug resistant cancer cells.