Natural products as a means of overcoming cisplatin chemoresistance in bladder cancer

Abstract

Cisplatin remains an integral part of the treatment for muscle invasive bladder cancer. A large number of patients do not respond to cisplatin-based chemotherapy and efficacious salvage regimens are limited. Immunotherapy has offered a second line of treatment; however, only approximately 20% of patients respond, and molecular subtyping of tumors indicates there may be significant overlap in those patients that respond to cisplatin and those patients that respond to immunotherapy. As such, restoring sensitivity to cisplatin remains a major hurdle to improving patient care. One potential source of compounds for enhancing cisplatin is naturally derived bioactive products such as phytochemicals, flavonoids and others. These compounds can activate a diverse array of different pathways, many of which can directly promote or inhibit cisplatin sensitivity. The purpose of this review is to understand current drug development in the area of natural products and to assess how these compounds may enhance cisplatin treatment in bladder cancer patients.

Keywords: Cisplatin; apoptosis; bladder cancer; natural products.

Figure 1

Mechanisms of cisplatin toxicity and resistance. Cisplatin is transported either actively by copper transporters such as CTR1 across the plasma membrane or passively through diffusion. Cisplatin can be actively transported out of the cell by metal transporters such as ATP7A and ATP7B and thus overexpression of these transporters is a mechanism of resistance. Cisplatin is hydrolyzed to its active form in the cytosol where it can bind proteins inducing oxidative stress or can be detoxified via cellular antioxidants like GSH. Active cisplatin binds purines on DNA which results in activation of p53 and the DNA damage response. P53 target genes like Bax and cellular stress from oxidative damage activate MOMP formation in the mitochondria, resulting in release of cytochrome c and activation of the apoptosome. Caspase3/7 cleave ICAD which release CAD and cleaves DNA leading to apoptosis. Black arrows notate events that promote toxicity, red arrows notate events that promote resistance. CTR1: copper transporter 1; Cis: cisplatin; GSH: glutathione; Bax: Bcl2 associated X-protein; tBid: truncated - BH3 domain interacting-domain death agonist; ATR: ataxia telengeicstasia and Rad3 related protein; CHK1: checkpoint kinase 1; Cyto C: cytochrome C; MTP: mitochondrial permeability transition pore; IAPs: inhibitors of apoptosis proteins; NRF2: nuclear factor erythroid-derived 2-like