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.

Curcumin–cisplatin chemotherapy: A novel strategy in promoting chemotherapy efficacy and reducing side effects

“…These compounds have the ability to stimulate a wide range of pathways, all of which can directly facilitate or impede cisplatin sensitivity. Curcumin in combination with cisplatin through downregulation of Bcl2 and survivin can induce apoptosis resulting in chemoresistance prevention to cisplatin (Rajendran et al, 2021). The resistance and toxicity mechanism to cisplatin is shown in Figure 5.…”

Natural bioactive compounds: a potential therapeutic strategy to sensitize bladder cancer to cisplatin treatment?

“…Several factors have been associated with resistance to cisplatin, including decreased intracellular drug concentration mediated by drug efflux pumps, alterations in DNA repair genes, and increased drug cytosolic inactivation [ 15 ] . I fully support their argument [ 14 ] that a greater understanding of the mechanisms of cisplatin activity and resistance, as well as the identification of potential biomarkers of response, is required so that we can select patients likely to respond to cisplatin and to improve strategies to fight resistance mechanisms. One such strategy is based on targeting the effectors and pathways involved in chemoresistance with natural compounds that can potentially synergize with platinum drugs, such as cisplatin.…”

“…In this issue of Cancer Drug Resistance , Rajendran et al [ 14 ] elegantly reviewed the mechanisms of cisplatin activity and resistance in BC and the potential of bioactive natural compounds, such as phytochemicals and flavonoids, to overcome this resistance and improve therapeutic response. As they pointed out [ 14 ] , resistance to cisplatin is a complex, multifactorial process that can be attributed to specific mechanisms intrinsic to BC biology or to general mechanisms common to different tumor types or drug pharmacokinetics. Several factors have been associated with resistance to cisplatin, including decreased intracellular drug concentration mediated by drug efflux pumps, alterations in DNA repair genes, and increased drug cytosolic inactivation [ 15 ] .…”

“…Nevertheless, to solve this problem, in recent years, many efforts have been focused on obtaining new promising bioavailable formulations or delivery strategies: liposomes, micelles, phospholipid complexes, microemulsions, nano-emulsions, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, biopolymer nanoparticles, and microgels [ 27 , 28 ] . Nonetheless, as proposed by Rajendran et al [ 14 ] , high quality pharmacokinetic and pharmacodynamic studies are required for proper dosing of these new compounds. Moreover, increasing our understanding of how these compounds work is critical to developing synthetic derivatives with improved pharmacokinetics and greater bioavailability and efficacy.…”

“…In conclusion, although cisplatin is a clinical mainstay for the treatment of MIBC, many tumors unfortunately develop resistance and are refractory to treatment. As Rajendran et al [ 14 ] pointed out, combination therapies using natural products represent a promising effective and novel strategy to overcome this resistance. For instance, the combination of curcumin and cisplatin could be a potential synergistic strategy to attenuate cisplatin-related adverse effects and decrease resistance.…”