Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer

Abstract

Summary Although cisplatin is one of the most common antineoplastic drug, its successful utilisation in cancer treatment is limited by the drug resistance. Multiple attempts have been made to find potential cisplatin chemosensitisers which would overcome cancer cells resistance thus improving antineoplastic efficacy. Autophagy modulation has become an important area of interest regarding the aforementioned topic. Autophagy is a highly conservative cellular self-digestive process implicated in response to multiple environmental stressors. The high basal level of autophagy is a common phenomenon in cisplatin-resistant cancer cells which is thought to grant survival benefit. However current evidence supports the role of autophagy in either promoting or limiting carcinogenesis depending on the context. This encourages the search of substances modulating the process to alleviate cisplatin resistance. Such a strategy encompasses not only simple autophagy inhibition but also harnessing the process to induce autophagy-dependent cell death. In this paper, we briefly describe the mechanism of cisplatin resistance with a special emphasis on autophagy and we give an extensive literature review of potential substances with cisplatin chemosensitising properties related to autophagy modulation.

Prodigiosin Sensitizes Sensitive and Resistant Urothelial Carcinoma Cells to Cisplatin Treatment

“…Generally, there is a strong relationship between autophagy and cisplatin resistance. Recently, Gąsiorkiewicz et al reviewed autophagy-modulating compounds that chemosensitize for cisplatin in cancer therapy [ 54 ]. Among these compounds are classical autophagy inhibitors, compounds with specific autophagy-related targets, and natural compounds.…”

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

“…More efforts in revealing anti-tumor activity of CP revealed that CP has the capacity of internalization in organelles, such as endoplasmic reticulum (ER), mitochondrion, lysosomes, and nucleus. This demonstrates that, in addition to DNA damage, CP can induce cell death by impairing homeostasis of vital organelles, such as ER and mitochondrion [19,20]. However, this impact may negatively affect anti-tumor activity of CP.…”

Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic–Linear–Dendritic Block Copolymers

“…In order to increase the therapeutic efficacy and reduce the side effects, CDDP is commonly used in combination with other drugs [ 51 ]. In this context, chloroquine (CQ), which has long been used as an anti-malarial and anti-rheumatic drug, sensitizes cancer cells to chemotherapeutic drugs through the prevention of autophagy [ 61 , 62 , 63 , 64 ]. As both CDDP and CQ are nonselective and can damage healthy tissues, reducing their effective doses and increasing delivery into tumor cells is key and can be accomplished by the encapsulation of the drugs in nanoparticles [ 30 , 65 ].…”

“…Interestingly, while simultaneous treatment with free drugs had a huge impact on both tumor and non-tumor cells, simultaneous treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and free CDDP resulted in high levels of cytotoxicity only against tumor cells. A possible explanation of this effect could be the reduced ability of Fdh to retain CQ encapsulations compared to tumor cells, as well as changes induced by cisplatin on membrane properties that reduce drug uptake and alter vesicular trafficking [ 62 , 88 , 89 ]. This opens the possibility of safely using the drugs simultaneously to achieve greater tumor cell killing without reducing the concentrations [ 85 , 90 ].…”