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.
Highlights
Bladder cancer (BCa) is a common solid tumor with high rates of morbidity and mortality, especially in patients with advanced disease
Pro-apoptotic proteins such as Bax and Bid that initiate the mitochondrial permeability transition pore (MTP) necessary for release of proapoptotic factors from the mitochondria are commonly downregulated or dysregulated in cancer such that there is implicit resistance to apoptosis[14,63]. This may be a potential reason for the observation that, in spite of the focus on apoptosis as a major mediator of cisplatin toxicity, clinical cisplatin administration is consistent with mixed cell death[24]
Natural products have been a major source of chemotherapeutic drugs and will likely continue to be so
Summary
Bladder cancer (BCa) is a common solid tumor with high rates of morbidity and mortality, especially in patients with advanced disease. Studies in breast cancer indicate E3330 enhances cisplatin resistance via blocking the pro-apoptotic response associated with DNA repair, and in contrast, suggests the lyase domain of polymerase ß is irrelevant, whereas knockdown of XRCC1 results in sensitivity to cisplatin due to increased DNA damage[55] Whether or not these mechanisms are universal between cancers remains in doubt; in BCa, it appears that BER may be a target for improving cisplatin-based therapy. Pro-apoptotic proteins such as Bax and Bid that initiate the mitochondrial permeability transition pore (MTP) necessary for release of proapoptotic factors from the mitochondria are commonly downregulated or dysregulated in cancer such that there is implicit resistance to apoptosis[14,63] This may be a potential reason for the observation that, in spite of the focus on apoptosis as a major mediator of cisplatin toxicity, clinical cisplatin administration is consistent with mixed cell death (apoptosis and necrosis)[24]. Given the diverse set of mechanisms associated with natural products, it will be imperative to define any potential benefit these agents may provide with immunotherapy
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