Cisplatin-induced pyroptosis: a double-edged sword in cancer treatment

Wenyang Lei; Wenting Yu; Yu Zhong; Ti Li; Hongjun Xiao; Shimin Zong

doi:10.1515/oncologie-2024-0132

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Cisplatin-induced pyroptosis: a double-edged sword in cancer treatment

Wenyang Lei , Wenting Yu , Yu Zhong , Ti Li , Hongjun Xiao and Shimin Zong

Published/Copyright: August 9, 2024

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From the journal Oncologie Volume 26 Issue 5

Abstract

Cancer is a major cause of death worldwide and a serious threat to human health. Cisplatin, a widely used first-line chemotherapeutic agent for various solid tumors, is renowned for its efficacy but is limited by significant cytotoxicity. Cisplatin triggers pyroptosis in tumor cells by activating Gasdermin proteins, thereby enhancing its anticancer efficacy. However, this same mechanism can induce pyroptosis in normal cells, causing inflammation and toxicity in healthy tissues, such as nephrotoxicity and ototoxicity. The objective of this review is to identify the major molecular targets for optimizing the cisplatin treatment window by summarizing recent advances in the pyroptosis caused by cisplatin in different cancer types and normal tissues. Among them, gasdermin D and gasdermin E are the main molecular targets involved in cisplatin-induced pyroptosis, and GSDMB also has similar effects. Future research directions include exploring targeted drug delivery systems and target regulating GSDMs (gasdermin protein family) to selectively modulate pyroptosis, thereby maximizing cisplatin’s anticancer effects while minimizing its side effects. Therefore, this review provides a comprehensive overview of cisplatin-induced pyroptosis, offering new insights into therapeutic strategies in cancer treatment.

Keywords: cancer treatment; cisplatin; pyroptosis; Garsdermin protein

Introduction

Pyroptosis is an inflammatory mode of cell death characterized by cell membrane disruption and pore formation, differing significantly from apoptosis, which maintains an intact cell membrane [1, 2]. Pyroptosis can occur via classical and non-classical pathways, depending on different mechanisms. The classical pathway involves cysteinyl aspartate specific proteinase-1 (caspase-1) and Gasdermin D (GSDMD), while non-classical pathways involve other cysteinyl aspartate specific proteinases (caspases) [3]. GSDMD, the first discovered gasdermin protein, forms pores in the plasma membrane upon cleavage by caspase-1, thereby inducing pyroptosis [4]. Other Gasdermin family members, such as gasdermin A (GSDMA) and gasdermin B (GSDMB), also possess pore-forming abilities and can directly induce pyroptosis [4]. DFNA5, initially associated with inherited sensorineural hearing loss, is cleaved by cysteinyl aspartate specific proteinase-3 (caspase-3) into an N-terminal fragment that induces pyroptosis and is thus termed gasdermin E (GSDME) [5], [6], [7]. Furthermore, lipopolysaccharides (LPS) can activate cysteinyl aspartate specific proteinase-8/9/11 (caspase-8/9/11) to promote GSDMD cleavage and induce pyroptosis, and granzyme A can cleave gasdermin B (GSDMB) to induce pyroptosis [8], [9], [10]. These studies highlight the complex mechanisms of pyroptosis, with new pathways continually being discovered.

Cisplatin (DDP), also known as cis-diamminedichloroplatinum (II), is extensively used to treat solid tumors such as ovarian, lung, head and neck squamous cell, and testicular cancers [11, 12]. It induces tumor cell death through apoptosis and pyroptosis [13]. Tumor cells often develop resistance to apoptosis, which can reduce cisplatin’s efficacy, whereas pyroptosis can circumvent this issue [14], [15], [16]. Pyroptosis occurs with the release of inflammatory factors that activate the immune system and inhibit tumor growth, thereby increasing tumor cell sensitivity to cisplatin and enhancing its therapeutic effects [14, 17]. Cisplatin-induced pyroptosis was found in various tumor cells, including non-small cell lung cancer (NSCLC) cells, esophageal squamous cell carcinoma (ESCC), and gastric cancer (GC) cells, characterized by cell swelling, decreased activity, and increased expression of pyroptosis-related proteins [18], [19], [20]. Cisplatin-induced pyroptosis has been implicated in many cancers, but it also induces pyroptosis in normal tissues such as oral squamous cell carcinoma perivascular tissues, renal tubular epithelial cells, and cochlear stria vascular cells, contributing to side effects like oral mucosal inflammation, nephrotoxicity, and ototoxicity [21], [22], [23]. Thus, research on cisplatin-induced pyroptosis focuses on enhancing cisplatin’s tumor-targeting ability while reducing its cytotoxic effects on normal tissues to improve cancer patient prognosis.

Cisplatin-induced pyroptosis in tumor cells

Cisplatin achieves anticancer effects primarily through apoptosis, but recent studies show it also induces pyroptosis to similar ends [24], [25], [26], [27]. Unlike apoptosis, pyroptosis involves the release of inflammatory factors, which can promote tumor growth by fostering a pro-inflammatory environment. The mechanisms of cisplatin-induced pyroptosis are complex (as shown in Table 1), and its roles in different malignancies require further exploration.

Table 1:

Mechanism and morphological changes of cisplatin-induced pyroptosis in tumor cells.

First author	Year	Tumor type	Experimental system				Mechanism of pyroptosis	Morphological changes of cells
First author	Year	Tumor type	Drug	Processing time	Dosage	Experimental object	Mechanism of pyroptosis	Morphological changes of cells
Cui et al. [28]	2023	Lung adenocarcinoma	DDP DDP	24 h 24 h	10 μM 5 μM	A549/DDP H1299, H1975 cell	NLRP3/caspase-1/GSDMB	The cell membrane forms macropores larger than 1 μm in diameter
Chen et al. [29]	2023	NSCLC	DDP DDP	24 h 24 h	50 μM 30 μM	A549 cell H460 cell	AMIGO2/PDK/Akt (T308)/caspase-8 or caspase-9/caspase-3/GSDME	Cells become round and shrink, membrane integrity is impaired, and large bubbles appear in the plasma membrane
Cheng et al. [30]	2022	NSCLC	Ophiopogon B (OP-B)	24 h	2.5 μM	A549/DDP cell	caspase-1/GSDMD	The cells were swollen to varying degrees, the cell plasma membrane was broken and the gas bubble was formed
Long et al. [31]	2021	NSCLC	DDP	–	10 μM	A549 cell	–	Cytoplasmic swelling and plasma membrane bubbles
Shi et al. [18]	2021	NSCLC	DDP	48 h	250 μM	A549 cell	miR-556-5p/NLPR3/caspase-1/GSDMD	–
Peng et al. [27]	2020	NSCLC	DDP	–	–	A549 cell	caspase-3/GSDME	–
Xu et al. [32]	2020	NSCLC	DDP	–	–	A549, H1299 cell	Smad-2/XIST/NLPR3/caspase-1/GSDMD	–
Zhang et al. [33]	2019	NSCLC	DDP	24 h	60 μM	A549 cell	caspase-3/GSDME	The membrane integrity of PI-positive cells was impaired, and there were large bubbles on the plasma membrane
Theivanthiran et al. [34]	2020	GC	DDP	24 h	50 μM	GC cells	caspase-3/GSDME	–
Li et al. [35]	2021	GC	DDP	48 h	200 μM	CR-GC	PD-L1/NLPR3	–
Ren et al. [19]	2020	GC	DDP	24 h	–	ACR-GC	miR-223-3P/LncRNA-ADAMTS9AS2/NLPR3/caspase-1	–
Li et al. [20]	2022	Esophageal squamous cell carcinoma	DDP DDP	24 h 24 h	20 μM 10 μM	KYSE30 KYSE510	CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3/GSDME	–
Zheng et al. [36]	2021	Esophageal squamous cell carcinoma	DDP	24 h	20 μM	KYSE30, KYSE450	STAT3β/caspase-3/GSDME	–
Yan et al. [37]	2021	Triple-negative breast cancer	DDP	48 h	9.952 μM	MDA-MB-231 cell	MEG3/NLRP3/caspase-1/GSDMD	Swelling of cells and membrane boundary ambiguity and cytoplasmic vacuolation
Li et al. [38]	2023	PDAC	DDP	24 h	–	PDAC cells	caspase-3/GSDME	Cell membrane bubble
Zi et al. [39]	2023	OSCC	DDP	24 h	20 μM	HN6, cal27 cell	caspase-3/GSDME	The tumor cell membrane bubbled
Huang et al. [21]	2020	OSCC	DDP DDP DDP	24 h 24 h 24 h	30 μM 20 μM 40 μM	NOK GSE HUVEC	caspase-3/GSDME	–
Yang et al. [40]	2022	Hepatocellular carcinoma	DDP	72 h	2.5 × 10⁻³ g·kg⁻¹·(3d)⁻¹	BALB/c mice	NLPR3/caspase-1/GSDMD	–
Wang et al. [41]	2021	Hepatocellular carcinoma	DDP	72 h	100 μM	HepG2/Hep3B	NLRP3/ASC/caspase-1/GSDMD	–
Westbom et al. [42]	2015	MM	DDP	24 h	100 μM	MM cell	NLPR3/caspase-1	–
Li et al. [43]	2020	NPC	DDP	12 h	5 μM	CNE-2Z cell	Bax/caspase-3/GSDME	–

Cisplatin-induced pyroptosis and non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the most common lung cancer types, with cisplatin chemotherapy as a primary treatment. However, long-term use leads to drug resistance. Recent studies suggest that cisplatin-induced pyroptosis offers new treatment strategies for NSCLC [44]. By activating caspase-3, cisplatin-induced pyroptosis in A549 cells, which is an NSCLC cell line, finally leads to GSDME cleavage [33]. Cells treated with cisplatin exhibit large membrane bubbles, while GSDME knockdown reduces such pyroptotic characteristics [33]. Moreover, SMAD2 gene silencing inhibits lncRNA XIST overexpression in NSCLC post-cisplatin intervention, upregulating NLRP3, caspase-1, and caspase-3, thus enhancing cisplatin-induced pyroptosis [32]. Overexpression of XIST inhibits pyroptosis, impacting tumor progression [32]. Additionally, Ophiopogon B (OP-B) treatment enhances cisplatin-induced pyroptosis in DDP-resistant A549 cells, indicated by cell swelling, plasma membrane rupture, and increased caspase-1 and GSDMD expression [30]. High GSDME expression correlates with increased sensitivity to cisplatin, lower cell viability, and promotes T-cell infiltration in tumor tissues, highlighting its potential as a lung cancer immunotherapy target [27].

In addition, pyroptosis can improve the sensitivity of tumor cells to cisplatin and reduce drug resistance. In one study, A549-DDP cells resistant to cisplatin were treated with APE1 inhibitor NO.0449-0145 and then showed typical pyroptosis morphological changes like cytoplasmic swelling with plasma membrane bubbles. This indicates that the use of NO.0449-0145 treatment can overcome cisplatin resistance in A549-DDP cells and make A549-DDP cells sensitive to cisplatin treatment [31]. Inhibition of miR-556-5pN increases NLRP3 expression in NSCLC cells, activating pyroptosis and enhancing cisplatin sensitivity [18]. Conversely, AMIGO overexpression reduces cisplatin-induced pyroptosis through the PDK1/Akt pathway, decreasing NSCLC cell sensitivity to cisplatin [29]. Overall, cisplatin-induced pyroptosis presents a new target to improve NSCLC sensitivity to cisplatin.

Cisplatin-induced pyroptosis and gastric cancer

Gastric cancer (GC) is prevalent in Asia, particularly in Japan, South Korea, and China, with cisplatin being a common first-line treatment [45], [46], [47]. Recent studies on pyroptosis offer new therapeutic targets for GC. LncRNA ADAMTS9/miR-223-3p axis triggers cisplatin-induced by activating NLRP3 inflammasome in cisplatin-resistant GC cells, enhancing cisplatin cytotoxicity and reducing GC resistance [19]. Dioscorea bulbifera L. extract, bisspore protein-B, induces pyroptosis by downregulating PD-L1 in cisplatin-treated GC, activating the NLRP3 inflammasome and enhancing cisplatin’s cytotoxic effects [35, 48]. MUC20 overexpression indicates a poor prognosis in malignant tumors. Silencing MUC20 in GC with cisplatin leads to typical pyroptosis morphology and increased caspase-3 and GSDME-N fragments, suggesting that downregulating cisplatin-induced pyroptosis may reduce GC sensitivity to cisplatin [34, 49, 50].

Cisplatin-induced pyroptosis and esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancer types in China, with cisplatin as the primary treatment. However, long-term use leads to strong drug resistance, resulting in suboptimal efficacy and prognosis [51, 52]. CAPN1/CAPN2 are potential ESCC prognosis biomarkers. By depleting CAPN1/CAPN2 and activating caspase-3/GSDME, cisplatin inducing pyroptosis in ESCC through CAPN1/CAPN2-Bak/BAX-caspase-9-caspase-3-GSDME axis [20]. STAT3β overexpression in ESCC also promotes cisplatin-induced pyroptosis, while in SHEE cells, which are the human immortalized normal esophageal epithelial cell line here, only high cisplatin concentrations induce pyroptosis [36].

Cisplatin-induced pyroptosis and other cancers

Research has shown that cisplatin-induced pyroptosis is involved in the development of various malignant tumors, though its role and mechanism differ across diseases. Cisplatin-induced pyroptosis in tumor cells can effectively control tumor progression and enhance the efficacy of chemotherapy drugs. For instance, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) deficiency are typical features of triple-negative breast cancer (TNBC) [53, 54]. TNBC has higher rates of recurrence and mortality than other breast cancer subtypes, with cisplatin-based systemic chemotherapy being the primary treatment [55]. Studies have observed significant cell swelling, membrane opacity, and cytoplasmic vacuolation in breast surgical specimens from TNBC patients undergoing cisplatin chemotherapy, indicating that cisplatin induces pyroptosis in TNBC [37]. It was observed in vivo xenograft tumor models that TNBC cells showed a dose-dependent decrease in cell viability under cisplatin treatment, and the cell membrane generated typical large bubble [37]. Finally, the researchers concluded that the above process was induced by the MEG3/NLRP3/caspase-1/GSDMD pathway activated by cisplatin [37].

Moreover, combined treatment with cisplatin and Inetetamab induced honeycomb pore changes in the membranes of lung adenocarcinoma (LUAD) cells, and activation of caspase-1/GSDMB signaling induced pyroptosis and decreased the viability of cells. And the genetic screening of LUAD patients found that patients with high expression of pyroptosis-related genes had a higher sensitivity to cisplatin [28].

Malignant mesothelioma (MM), typically caused by asbestos exposure, is resistant to chemotherapy and radiotherapy. Cisplatin treatment of Hmeso (epithelioid) and H2373 (fibrosarcoma) cells increases NLRP3/caspase-1 protein levels, inducing pyroptosis and releasing inflammatory factors like 1L-18 and IL-1β, thereby reducing the viability of these cells [42].

Additionally, cisplatin-induced pyroptosis enhances the sensitivity of tumor cells to cisplatin and reduces drug resistance [56]. Nasopharyngeal carcinoma (NPC) is a common disease in southern China and Southeast Asia, which has been shown to respond positively to cisplatin [57]. Cisplatin treatment can prolong the survival time of patients with advanced nasopharyngeal carcinoma [58]. Bix-01294 is a diazoquinazolinamide derivative, which can activate Bax/caspase-3/GSDME in NPC cells to promote cisplatin-induced pyroptosis [43].

Primary liver cancer is a rapidly progressing and highly fatal malignancy in China [59, 60]. Clinically, liver cancer treatment often combines surgery and cisplatin chemotherapy, which can lead to recurrence and reduce the quality of life for patients [61]. Incomplete radiofrequency ablation (IRFA) treatment at 42–48 °C enhances cisplatin-induced pyroptosis in hepatocellular carcinoma (HCC) by regulating the HSP70/NLRP3/ASC/caspase-1/GSDMD pathway, thereby increasing HCC sensitivity to cisplatin [41]. Other studies have found that combining Shenqi tumor-suppressing prescription with cisplatin downregulates pyroptosis-related protein factors like NLRP3, caspase-1, and GSDMD protein levels in H22 liver cancer mice, inhibiting pyroptosis, reducing inflammatory responses, and mitigating cisplatin side effects [40]. However, pyroptosis remains an important mechanism for controlling liver cancer progression and optimizing cisplatin-induced pyroptosis to achieve the best therapeutic outcomes requires further study.

Pancreatic ductal adenocarcinoma (PDAC) is a highly resistant and difficult-to-diagnose malignancy [62]. After cisplatin treatment, caspase-3 and GSDME cleavage increase in PDAC cells, leading to LDH (lactate dehydrogenase) release and plasma membrane rupture, indicating pyroptosis and inhibited cell growth [38]. However, GSDME knockdown significantly increases PDAC cell sensitivity to cisplatin [38]. This suggests that while cisplatin-induced pyroptosis in tumor cells plays a crucial role in inhibiting PDAC development, it also contributes to cisplatin resistance, necessitating further investigation into its specific role.

In the treatment of oral squamous cell carcinoma (OSCC), cisplatin-induced oral mucosal inflammation and ulcers cause significant pain and hinder subsequent treatments [63]. Recent studies confirm that cisplatin activates caspase-3/GSDME to induce pyroptosis, with cytoplasmic bubbling observed in HN6 and Cal27 cells. Overexpression of GSDME enhances cisplatin-induced pyroptosis [39]. Another study noted increased GSDME-N fragments and typical pyroptotic changes in normal cells of OSCC patients treated with cisplatin [21]. Cells with GSDME overexpression exhibited higher mortality and LDH release. Vitamin D treatment downregulates caspase-3 expression, reducing GSDME cleavage and LDH release, thus inhibiting cisplatin-induced pyroptosis in normal cells and increasing resistance to cisplatin in normal tissues. Since systemic inhibition of GSDME cleavage is unattainable, it is proposed that inhibiting the caspase-3 pathway can prevent pyroptosis in normal cells of OSCC patients undergoing cisplatin treatment, reducing platinum drug side effects [21]. While cisplatin induces cleavage of both GSDME and GSDMD, their roles in cisplatin chemotherapy side effects in OSCC patients remain unclear.

Cisplatin induces pyroptosis in normal cells during tumor treatment

Many patients with malignant tumors experience severe complications following cisplatin treatment, such as acute kidney injury and sensorineural deafness [64], [65], [66]. Recent studies have found that cisplatin induces pyroptosis in renal tubular epithelial cells and cochlear striate border cells [22, 67]. This cytotoxicity is closely related to multiple molecular pathways (as shown in Table 2). Further exploration may provide new strategies for mitigating the side effects of cisplatin.

Table 2:

Mechanism and morphological changes of cisplatin-induced pyroptosis in normal cells.

First author	Year	Experimental object	Experimental system			Mechanism of pyroptosis	Morphological changes of cells
First author	Year	Experimental object	Drug	Treatment time or method	Dosage	Mechanism of pyroptosis	Morphological changes of cells
Zheng [68]	2024	HK2cell	DDP	48 h	5 μM	GSDME	–
Zhu et al. [69]	2023	HK2cell	DDP	24 h	20 μM	miR-122/ELAVL1/NLRP3/Caspase-1/GSDMD	–
Wan et al. [70]	2023	NRK-52E cell	DDP	24 h	10 μM	NLRP3/Caspase-1/GSDMD	Pyroptotic bodies
Yu et al. [22]	2022	MCs	DDP	24 h	5 μM	TXNIP/NLRP3/Caspase-1/GSDMD	The cell membrane showed large pore changes
Xia et al. [71]	2021	HK-2 cell	DDP	24 h	100 μM	Caspase-3/GSDME Caspase-1/GSDMD	The cell swells and the cell membrane forms a large number of pores
Shen et al. [72]	2021	HK-2 cell	DDP	48 h	20 μM	ROS/JNK/caspase-3/GSDME	Bubbles appear on cell membranes
Xu et al. [73]	2021	H9c2 cell	DDP	72 h	5 μM	NLRP3/Caspase-1/GSDMD	–
Li et al. [74]	2020	RTEC	DDP	24 h	50 μM	Caspase-1 or caspase-11/GSDMD	The cells showed swelling and marked pore formation in the membrane
Badr et al. [23]	2023	Rat	DDP	Intraperitoneal injection	7 mg/kg	TLR4/NLPR3/Caspase-1/GSDMD	–
Tonnus et al. [67]	2022	Mouse	DDP	Intraperitoneal injection	20 mg/kg	GSDMD	–
Jiang et al. [75]	2021	Mouse	DDP	Intraperitoneal injection	20 mg/kg	NLRP3/Caspase-1/GSDMD	–

Nephrotoxicity

Cisplatin can cause dose-dependent nephrotoxicity, with 30 % of patients suffering varying degrees of kidney injury after treatment [76], [77], [78]. Studies have shown that cisplatin regulates the ROS/JNK/caspase-3/GSDME pathway in HK-2 cells, inducing pyroptosis with visible bubbles in the plasma membrane [72]. Knockdown of GSDME reduces pyroptosis characteristics in HK-2 cells [72]. Another study confirmed these findings, showing a dose-dependent increase in caspase-3/GSDME-N and caspase-1/GSDMD expression in mouse HK-2 cells treated with cisplatin. This increase was accompanied by elevated IL-1β and LDH levels and formed large diameter pores in the cell membrane [73]. These results indicated that cisplatin exacerbates inflammation in renal tubular epithelial cells, leading to acute kidney injury (AKI) by inducing pyroptosis in HK-2 cells.

Furthermore, mice with GSDME deficiency showed significant recovery of renal function, with reduced levels of serum creatinine, blood urea nitrogen, and cystatin C 72 h after cisplatin injection. The levels of inflammatory factors IL-1β and IL-6 were also reduced, suggesting that GSDME may be one of the potential targets for AKI treatment [71]. Conversely, transfection of GSDMD-N into renal tubular epithelial cells (RETC) of mice treated with cisplatin increased the levels of IL-1β, IL-6 and LDH, reduced cell viability, and caused cell membrane porosity with large bubbles. This indicates that cisplatin-induced GSDMD cleavage triggers pyroptosis and inflammation in RETC, contributing to AKI [74].

Other studies suggest that vitamin D receptor (VDR) alleviates AKI by downregulating NLRP3/caspase-1/GSDMD pathway proteins [75]. N-acetylcysteine (NAC) and chlorogenic acid (CGA) inhibit cisplatin-induced TLR4/NLRP3/IL-1β and caspase-1/GSDMD signaling, reducing cell pyroptosis and cisplatin-induced nephrotoxicity [23]. In addition, Dex and HucMSC-Ex Ininhibit NLRP-3/caspase-1 signaling, in order to reduce the release of inflammatory factors and alleviate cisplatin-mediated pyroptosis in rat renal tubular epithelial cells [68, 70]. It was also found that miR-122 inhibited BUN, cNF-α, and IL-1β caused by cisplatin by ELAVL1, prevented cisplatin-induced cell pyroptosis and reduced kidney injury [69].

However, a contrary study found that GSDMD-knockout mice were lower tolerance to cisplatin induced renal tubule injury and had a higher mortality rate compared to wild-type mice. This study suggested that GSDMD deficiency increases susceptibility to cisplatin-induced AKI. Interestingly, mixed lineage kinase domain-like protein (MLKL) combined with GSDMD reversed this high sensitivity, and upregulating the GSDMD gene in renal peritubular cells inhibited AKI development after cisplatin treatment [67].

Ototoxicity

Cisplatin can enter the inner ear through the blood-labyrinth barrier and accumulate in the cochlea, leading to hearing loss in patients [79]. Cisplatin primarily damages the stria vascularis (SV), the organ of Corti, and the spiral ganglia of the cochlea. As the concentration of cisplatin increases, the damage to the cochlea intensifies, ultimately resulting in irreversible hearing loss [80, 81]. Previous studies have suggested that oxidative stress and inflammation are the main mechanisms underlying cisplatin ototoxicity [82]. It has been shown that reactive oxygen species (ROS) accumulation can cause irreversible damage to the cochlea, and cisplatin induces ROS accumulation, leading to oxidative stress in the cochlear environment [83, 84]. However, no studies have demonstrated that antioxidants can effectively prevent cisplatin-induced hearing loss.

Recent research has confirmed that cisplatin induces pyroptosis in rat cochlear stria vascularis marginal cells by activating the NLRP3 inflammasome [22]. As the concentration of cisplatin increases, marginal cell membranes break and form bubble-like structures. With the release of LDH and IL-1β, the expression levels of caspase-1/GSDMD protein increased, which indicates that cisplatin induces pyroptosis in marginal cells [22]. Pyroptosis may represent a new research direction for understanding cisplatin ototoxicity, but few relevant animal studies exist, and the specific mechanisms require further investigation.

Cardiotoxicity

Cisplatin-induced cardiotoxicity is a common side effect in anticancer therapy. Oxidative stress and mitochondrial damage are considered the main mechanisms of cisplatin-induced cardiotoxicity. Studies have shown that pyroptosis may also play a significant role [85], [86], [87]. It is believed that cisplatin induces pyroptosis in mouse cardiomyocytes via the NLRP3/caspase-1/GSDMD signaling pathway, resulting in increased LDH release and significantly elevated serum CK-MB levels. Wogonin has been shown to alleviate cisplatin-induced pyroptosis in mouse cardiomyocytes. Thus, inhibiting cisplatin-induced pyroptosis may offer a new therapeutic approach to reducing cardiotoxicity [73].

Discussion

Pyroptosis disrupts the integrity of the cell membrane and prompts the release of various inflammatory mediators, including IL-1β and IL-18 [88]. This process is fundamentally different from apoptosis and necrosis. These systemic inflammatory responses are considered resistant to the immunosuppression of the tumor microenvironment (TME), thus it is generally believed that tumor cell pyroptosis can inhibit tumor development [89, 90]. Additionally, in the early stages of tumorigenesis, pyroptosis supports the formation of TME and accelerates tumor cell growth by inducing inflammatory response [32, 91]. Therefore, we speculate that mitigating pyroptosis and controlling early inflammation may inhibit initial tumor development. However, since most tumors lack obvious symptoms in the early stages, identifying pyroptosis markers to detect its occurrence and finding new targets to intervene in pyroptosis may be innovative strategies for preventing tumor development.

Previous studies have suggested that cisplatin can induce pyroptosis in tumor cells to control tumor development, but it also causes damage to normal cells [18, 29, 49, 71, 73]. It is necessary to limit the range of cisplatin’s action and precisely target tumor cells. Additionally, it is important to identify specific targets of cisplatin-induced tumor cell pyroptosis to protect normal cells and reduce cisplatin’s cytotoxicity. Furthermore, extensive previous studies have confirmed that inducing pyroptosis can increase the sensitivity of NSCLC, ESCC, NPC, and other tumor cells to cisplatin, thereby reducing their drug resistance [18, 19, 30, 33, 38, 41, 43, 50]. In contrast, pyroptosis facilitated by GSDME decreases PDAC cells’ responsiveness to cisplatin [38]. Moreover, the mechanism of pyroptosis mediated by GSDMD/GSDME is complex (as shown in Figure 1). Therefore, exploring its role in the resistance mechanisms of tumor cells to cisplatin, as well as identifying other factors that regulate the sensitivity of tumor cells to cisplatin and reduce its cytotoxicity to normal cells, is the next research direction.

Figure 1:

!Molecular mechanism of pyroptosis induced by cisplatin. Note: The protein molecules included in the figure are as follows: GSDMD, gasdermin D; GSDME, gasdermin E; caspase-1, cysteinyl aspartate specific proteinase-1; caspase-3, cysteinyl aspartate specific proteinase-3; miR-223-3P, MicroRNA-223-3P; LncRNA-ADAMTS9-AS2, long non-coding RNA ADAMSTS9-AS2; miR-556-5P, MicroRNA-556-5P; Smad-2, recombinant mothers against decapentaplegic Homolog 2; XIST, X inactive-specific transcript; TXNIP, thioredoxin-interacting protein; PD-L1, programmed cell death 1 ligand 1; MEG3, maternally expressed gene 3; Ros, reactive oxygen species; JNK, c-Jun N-terminal kinase; STAT3β, signal transducer and activator of transcription 3β; CAPN1/CAPN2, recombinant Calpain 1/2; BAK/BAX, BCL2-associated K/X; caspase-9, cysteinyl aspartate specific proteinase-9; PDK-1: 3-phosphoinositide-dependent protein kinase 1; PKB, Akt: protein kinase B; caspase-8, cysteinyl aspartate specific proteinase-8.

Conclusions

Currently, most experiments are limited to studying tumor cell lines in vitro, with few animal studies available. Cisplatin-induced pyroptosis indeed reduces tumor cell viability and inhibits tumor cell growth in vitro. However, the specific mechanism of cisplatin-induced pyroptosis in vivo, whether the inflammatory response caused by pyroptosis promotes tumor growth, effectively kills tumor cells or expands the cytotoxicity of cisplatin, requires further research, especially to understand its effects on normal tissues. In conclusion, cisplatin-induced pyroptosis is closely related to various types of malignant tumors. Further animal and in vivo experiments are needed to target tumor cells while minimizing harm to normal tissues. Nevertheless, it can provide new insights for anticancer therapy.

Corresponding authors: Hongjun Xiao and Shimin Zong, Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, E-mail: xhjent_whxh@hust.edu.cn (H. Xiao), 2018xh0090@hust.edu.cn (S. Zong)

Wenyang Lei and Wenting Yu contributed equally to this work.

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 82101229

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: Wenyang Lei and Wenting Yu are co-first authors of the article. They reviewed the references and wrote the manuscript. Yu Zhong and Ting Li edited and corrected the manuscript. Hongjun Xiao and Shiming Zong planned the manuscript, they are the corresponding authors of the article.
Competing interests: Authors state no conflict of interest.
Research funding: This work was supported by grants from the National Natural Science Foundation of China [Grant numbers 82071057, 82101229] and Key Research and Development Program of Hubei Province Project [Grant 2021BCA144].
Data availability: Not applicable.

References

1. Johnson, DC, Taabazuing, CY, Okondo, MC, Chui, AJ, Rao, SD, Brown, FC, et al.. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med 2018;24:1151–6. https://doi.org/10.1038/s41591-018-0082-y.Search in Google Scholar PubMed PubMed Central

2. Silva, MT. Bacteria-induced phagocyte secondary necrosis as a pathogenicity mechanism. J Leukoc Biol 2010;88:885–96. https://doi.org/10.1189/jlb.0410205.Search in Google Scholar PubMed

3. Wang, Y, Kanneganti, TD. From pyroptosis, apoptosis and necroptosis to PANoptosis: a mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J 2021;19:4641–57. https://doi.org/10.1016/j.csbj.2021.07.038.Search in Google Scholar PubMed PubMed Central

4. Kovacs, SB, Miao, EA. Gasdermins: effectors of pyroptosis. Trends Cell Biol 2017;27:673–84. https://doi.org/10.1016/j.tcb.2017.05.005.Search in Google Scholar PubMed PubMed Central

5. Nishio, A, Noguchi, Y, Sato, T, Naruse, TK, Kimura, A, Takagi, A, et al.. A DFNA5 mutation identified in Japanese families with autosomal dominant hereditary hearing loss. Ann Hum Genet 2014;78:83–91. https://doi.org/10.1111/ahg.12053.Search in Google Scholar PubMed

6. Rogers, C, Fernandes-Alnemri, T, Mayes, L, Alnemri, D, Cingolani, G, Alnemri, ES. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun 2017;8:14128. https://doi.org/10.1038/ncomms14128.Search in Google Scholar PubMed PubMed Central

7. Wang, Y, Gao, W, Shi, X, Ding, J, Liu, W, He, H, et al.. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 2017;547:99–103. https://doi.org/10.1038/nature22393.Search in Google Scholar PubMed

8. He, WT, Wan, H, Hu, L, Chen, P, Wang, X, Huang, Z, et al.. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res 2015;25:1285–98. https://doi.org/10.1038/cr.2015.139.Search in Google Scholar PubMed PubMed Central

9. Zhou, Z, He, H, Wang, K, Shi, X, Wang, Y, Su, Y, et al.. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 2020;368:eaaz7548. https://doi.org/10.1126/science.aaz7548.Search in Google Scholar PubMed

10. Shi, J, Zhao, Y, Wang, Y, Gao, W, Ding, J, Li, P, et al.. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014;514:187–92. https://doi.org/10.1038/nature13683.Search in Google Scholar PubMed

11. Dasari, S, Tchounwou, PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014;740:364–78. https://doi.org/10.1016/j.ejphar.2014.07.025.Search in Google Scholar PubMed PubMed Central

12. Qi, L, Luo, Q, Zhang, Y, Jia, F, Zhao, Y, Wang, F. Advances in toxicological research of the anticancer drug cisplatin. Chem Res Toxicol 2019;32:1469–86. https://doi.org/10.1021/acs.chemrestox.9b00204.Search in Google Scholar PubMed

13. Dasari, S, Njiki, S, Mbemi, A, Yedjou, CG, Tchounwou, PB. Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy. Int J Mol Sci 2022;23:1532. https://doi.org/10.3390/ijms23031532.Search in Google Scholar PubMed PubMed Central

14. Fang, Y, Tian, S, Pan, Y, Li, W, Wang, Q, Tang, Y, et al.. Pyroptosis: a new Frontier in cancer. Biomed Pharmacother 2020;121:109595. https://doi.org/10.1016/j.biopha.2019.109595.Search in Google Scholar PubMed

15. Yang, J, Ding, J. Nanoantidotes: a detoxification system more applicable to clinical practice. BME Front 2023;2023:0020. https://doi.org/10.34133/bmef.0020.Search in Google Scholar PubMed PubMed Central

16. Yang, J, Su, T, Zou, H, Yang, G, Ding, J, Chen, X. Spatiotemporally targeted polypeptide nanoantidotes improve chemotherapy tolerance of cisplatin. Angew Chem Int Ed Engl 2022;61:e202211136. https://doi.org/10.1002/ange.202211136.Search in Google Scholar

17. Rao, Z, Zhu, Y, Yang, P, Chen, Z, Xia, Y, Qiao, C, et al.. Pyroptosis in inflammatory diseases and cancer. Theranostics 2022;12:4310–29. https://doi.org/10.7150/thno.71086.Search in Google Scholar PubMed PubMed Central

18. Shi, F, Zhang, L, Liu, X, Wang, Y. Knock-down of microRNA miR-556-5p increases cisplatin-sensitivity in non-small cell lung cancer (NSCLC) via activating NLR family pyrin domain containing 3 (NLRP3)-mediated pyroptotic cell death. Bioengineered 2021;12:6332–42. https://doi.org/10.1080/21655979.2021.1971502.Search in Google Scholar PubMed PubMed Central

19. Ren, N, Jiang, T, Wang, C, Xie, S, Xing, Y, Piao, D, et al.. LncRNA ADAMTS9-AS2 inhibits gastric cancer (GC) development and sensitizes chemoresistant GC cells to cisplatin by regulating miR-223-3p/NLRP3 axis. Aging (Albany NY) 2020;12:11025–41. https://doi.org/10.18632/aging.103314.Search in Google Scholar PubMed PubMed Central

20. Li, RY, Zheng, ZY, Li, ZM, Heng, JH, Zheng, YQ, Deng, DX, et al.. Cisplatin-induced pyroptosis is mediated via the CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME axis in esophageal cancer. Chem Biol Interact 2022;361:109967. https://doi.org/10.1016/j.cbi.2022.109967.Search in Google Scholar PubMed

21. Huang, Z, Zhang, Q, Wang, Y, Chen, R, Wang, Y, Huang, Z, et al.. Inhibition of caspase-3-mediated GSDME-derived pyroptosis aids in noncancerous tissue protection of squamous cell carcinoma patients during cisplatin-based chemotherapy. Am J Cancer Res 2020;10:4287–307.Search in Google Scholar

22. Yu, W, Zong, S, Zhou, P, Wei, J, Wang, E, Ming, R, et al.. Cochlear marginal cell pyroptosis is induced by cisplatin via NLRP3 inflammasome activation. Front Immunol 2022;13:823439. https://doi.org/10.3389/fimmu.2022.823439.Search in Google Scholar PubMed PubMed Central

23. Badr, AM, Al-Kharashi, LA, Attia, H, Alshehri, S, Alajami, HN, Ali, RA, et al.. TLR4/Inflammasomes cross-talk and pyroptosis contribute to N-acetyl cysteine and chlorogenic acid protection against cisplatin-induced nephrotoxicity. Pharmaceuticals 2023;16:337. https://doi.org/10.3390/ph16030337.Search in Google Scholar PubMed PubMed Central

24. Liu, L, Fan, J, Ai, G, Liu, J, Luo, N, Li, C, et al.. Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biol Res 2019;52:37. https://doi.org/10.1186/s40659-019-0243-6.Search in Google Scholar PubMed PubMed Central

25. Shi, L, Mei, Y, Duan, X, Wang, B. Effects of cisplatin combined with metformin on proliferation and apoptosis of nasopharyngeal carcinoma cells. Comput Math Methods Med 2022;2022:2056247–6. https://doi.org/10.1155/2022/2056247.Search in Google Scholar PubMed PubMed Central

26. Abdel-Fatah, TM, Perry, C, Moseley, P, Johnson, K, Arora, A, Chan, S, et al.. Clinicopathological significance of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in oestrogen-receptor-positive breast cancer. Breast Cancer Res Treat 2014;143:411–21. https://doi.org/10.1007/s10549-013-2820-7.Search in Google Scholar PubMed

27. Peng, Z, Wang, P, Song, W, Yao, Q, Li, Y, Liu, L, et al.. GSDME enhances cisplatin sensitivity to regress non-small cell lung carcinoma by mediating pyroptosis to trigger antitumor immunocyte infiltration. Signal Transduct Target Ther 2020;5:159. https://doi.org/10.1038/s41392-020-00274-9.Search in Google Scholar PubMed PubMed Central

28. Cui, J, He, Y, Zhu, F, Gong, W, Zuo, R, Wang, Y, et al.. Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma. Int J Biol Sci 2023;19:4061–81. https://doi.org/10.7150/ijbs.82980.Search in Google Scholar PubMed PubMed Central

29. Chen, LK, Lin, SP, Xie, YH, Tan, XP, Xiong, BH, Zeng, XF, et al.. AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer. J Cell Mol Med 2023;27:2412–23. https://doi.org/10.1111/jcmm.17827.Search in Google Scholar PubMed PubMed Central

30. Cheng, Z, Li, Z, Gu, L, Li, L, Gao, Q, Zhang, X, et al.. Ophiopogonin B alleviates cisplatin resistance of lung cancer cells by inducing Caspase-1/GSDMD dependent pyroptosis. J Cancer 2022;13:715–27. https://doi.org/10.7150/jca.66432.Search in Google Scholar PubMed PubMed Central

31. Long, K, Gu, L, Li, L, Zhang, Z, Li, E, Zhang, Y, et al.. Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer. Cell Death Dis 2021;12:503. https://doi.org/10.1038/s41419-021-03804-7.Search in Google Scholar PubMed PubMed Central

32. Xu, X, Zhou, X, Chen, Z, Gao, C, Zhao, L, Cui, Y. Silencing of lncRNA XIST inhibits non-small cell lung cancer growth and promotes chemosensitivity to cisplatin. Aging (Albany NY) 2020;12:4711–26. https://doi.org/10.18632/aging.102673.Search in Google Scholar PubMed PubMed Central

33. Zhang, CC, Li, CG, Wang, YF, Xu, LH, He, XH, Zeng, QZ, et al.. Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis 2019;24:312–25. https://doi.org/10.1007/s10495-019-01515-1.Search in Google Scholar PubMed

34. Theivanthiran, B, Evans, KS, DeVito, NC, Plebanek, M, Sturdivant, M, Wachsmuth, LP, et al.. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest 2020;130:2570–86. https://doi.org/10.1172/jci133055.Search in Google Scholar PubMed PubMed Central

35. Li, C, Qiu, J, Xue, Y. Low-dose diosbulbin-B (DB) activates tumor-intrinsic PD-L1/NLRP3 signaling pathway mediated pyroptotic cell death to increase cisplatin-sensitivity in gastric cancer (GC). Cell Biosci 2021;11:38. https://doi.org/10.1186/s13578-021-00548-x.Search in Google Scholar PubMed PubMed Central

36. Zheng, ZY, Yang, PL, Li, RY, Liu, LX, Xu, XE, Liao, LD, et al.. STAT3β disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma. Cancer Lett 2021;522:171–83. https://doi.org/10.1016/j.canlet.2021.09.035.Search in Google Scholar PubMed

37. Yan, H, Luo, B, Wu, X, Guan, F, Yu, X, Zhao, L, et al.. Cisplatin induces pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in triple-negative breast cancer. Int J Biol Sci 2021;17:2606–21. https://doi.org/10.7150/ijbs.60292.Search in Google Scholar PubMed PubMed Central

38. Li, S, Yue, M, Xu, H, Zhang, X, Mao, T, Quan, M, et al.. Chemotherapeutic drugs-induced pyroptosis mediated by gasdermin E promotes the progression and chemoresistance of pancreatic cancer. Cancer Lett 2023;564:216206. https://doi.org/10.1016/j.canlet.2023.216206.Search in Google Scholar PubMed

39. Zi, M, Xingyu, C, Yang, C, Xiaodong, S, Shixian, L, Shicheng, W. Improved antitumor immunity of chemotherapy in OSCC treatment by Gasdermin-E mediated pyroptosis. Apoptosis 2023;28:348–61. https://doi.org/10.1007/s10495-022-01792-3.Search in Google Scholar PubMed

40. Yang, M, Duan, Y, Jia, Y, Bai, M, Zhu, Z, Li, Y, et al.. Mechanism of Shenqi yiliu prescription combined with cisplatin on H22 liver cancer-bearing mice based on NLRP3/caspase-1/GSDMD pyroptosis pathway. Chin J Exp Tradit Med Form 2023;29:114–22.Search in Google Scholar

41. Wang, F, Xu, C, Li, G, Lv, P, Gu, J. Incomplete radiofrequency ablation induced chemoresistance by up-regulating heat shock protein 70 in hepatocellular carcinoma. Exp Cell Res 2021;409:112910. https://doi.org/10.1016/j.yexcr.2021.112910.Search in Google Scholar PubMed

42. Westbom, C, Thompson, JK, Leggett, A, MacPherson, M, Beuschel, S, Pass, H, et al.. Inflammasome modulation by chemotherapeutics in malignant mesothelioma. PLoS One 2015;10:e0145404. https://doi.org/10.1371/journal.pone.0145404.Search in Google Scholar PubMed PubMed Central

43. Li, Q, Wang, M, Zhang, Y, Wang, L, Yu, W, Bao, X, et al.. BIX-01294-enhanced chemosensitivity in nasopharyngeal carcinoma depends on autophagy-induced pyroptosis. Acta Biochim Biophys Sin 2020;52:1131–9. https://doi.org/10.1093/abbs/gmaa097.Search in Google Scholar PubMed

44. Bray, F, Ferlay, J, Soerjomataram, I, Siegel, RL, Torre, LA, Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. https://doi.org/10.3322/caac.21492.Search in Google Scholar PubMed

45. Ye, J, Ren, Y, Chen, J, Song, W, Chen, C, Cai, S, et al.. Prognostic significance of preoperative and postoperative complement C3 depletion in gastric cancer: a three-year survival investigation. BioMed Res Int 2017;2017:2161840–9. https://doi.org/10.1155/2017/2161840.Search in Google Scholar PubMed PubMed Central

46. Ward, TA, McHugh, PJ, Durant, ST. Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes. PLoS One 2017;12:e0179278. https://doi.org/10.1371/journal.pone.0179278.Search in Google Scholar PubMed PubMed Central

47. Lee, SD, Yu, D, Lee, DY, Shin, HS, Jo, JH, Lee, YC. Upregulated microRNA-193a-3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells. Cancer Sci 2019;110:662–73. https://doi.org/10.1111/cas.13894.Search in Google Scholar PubMed PubMed Central

48. Li, C, Li, M, Xue, Y. Downregulation of CircRNA CDR1as specifically triggered low-dose Diosbulbin-B induced gastric cancer cell death by regulating miR-7-5p/REGγ axis. Biomed Pharmacother 2019;120:109462. https://doi.org/10.1016/j.biopha.2019.109462.Search in Google Scholar PubMed

49. Xue, B, Guo, WM, Jia, JD, Kadeerhan, G, Liu, HP, Bai, T, et al.. MUC20 as a novel prognostic biomarker in ccRCC correlating with tumor immune microenvironment modulation. Am J Cancer Res 2022;12:695–712.Search in Google Scholar

50. Fu, L, Yonemura, A, Yasuda-Yoshihara, N, Umemoto, T, Zhang, J, Yasuda, T, et al.. Intracellular MUC20 variant 2 maintains mitochondrial calcium homeostasis and enhances drug resistance in gastric cancer. Gastric Cancer 2022;25:542–57. https://doi.org/10.1007/s10120-022-01283-z.Search in Google Scholar PubMed

51. Sung, H, Ferlay, J, Siegel, RL, Laversanne, M, Soerjomataram, I, Jemal, A, et al.. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49. https://doi.org/10.3322/caac.21660.Search in Google Scholar PubMed

52. Li, W, Zhang, L, Guo, B, Deng, J, Wu, S, Li, F, et al.. Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFκB/c-Myc signaling in female esophageal carcinoma. Mol Cancer 2019;18:22. https://doi.org/10.1186/s12943-019-0949-7.Search in Google Scholar PubMed PubMed Central

53. Li, Y, Zhang, H, Merkher, Y, Chen, L, Liu, N, Leonov, S, et al.. Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol 2022;15:121. https://doi.org/10.1186/s13045-022-01341-0.Search in Google Scholar PubMed PubMed Central

54. Leon-Ferre, RA, Goetz, MP. Advances in systemic therapies for triple negative breast cancer. BMJ 2023;381:e071674. https://doi.org/10.1136/bmj-2022-071674.Search in Google Scholar PubMed

55. Lin, NU, Vanderplas, A, Hughes, ME, Theriault, RL, Edge, SB, Wong, YN, et al.. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 2012;118:5463–72. https://doi.org/10.1002/cncr.27581.Search in Google Scholar PubMed PubMed Central

56. Chen, YP, Chan, ATC, Le, QT, Blanchard, P, Sun, Y, Ma, J. Nasopharyngeal carcinoma. Lancet 2019;394:64–80. https://doi.org/10.1016/s0140-6736(19)30956-0.Search in Google Scholar PubMed

57. Chang, ET, Ye, W, Zeng, YX, Adami, HO. The evolving epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2021;30:1035–47. https://doi.org/10.1158/1055-9965.epi-20-1702.Search in Google Scholar PubMed

58. Li, WZ, Lv, X, Hu, D, Lv, SH, Liu, GY, Liang, H, et al.. Effect of induction chemotherapy with paclitaxel, cisplatin, and capecitabine vs cisplatin and fluorouracil on failure-free survival for patients with stage IVA to IVB nasopharyngeal carcinoma: a multicenter phase 3 randomized clinical trial. JAMA Oncol 2022;8:706–14. https://doi.org/10.1001/jamaoncol.2022.0122.Search in Google Scholar PubMed PubMed Central

59. Forner, A, Reig, M, Bruix, J. Hepatocellular carcinoma. Lancet 2018;391:1301–14. https://doi.org/10.1016/s0140-6736(18)30010-2.Search in Google Scholar PubMed

60. Giraud, J, Chalopin, D, Blanc, JF, Saleh, M. Hepatocellular carcinoma immune landscape and the potential of immunotherapies. Front Immunol 2021;12:655697. https://doi.org/10.3389/fimmu.2021.655697.Search in Google Scholar PubMed PubMed Central

61. Tabrizian, P, Jibara, G, Shrager, B, Schwartz, M, Roayaie, S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg 2015;261:947–55. https://doi.org/10.1097/sla.0000000000000710.Search in Google Scholar

62. Klein, AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021;18:493–502. https://doi.org/10.1038/s41575-021-00457-x.Search in Google Scholar PubMed PubMed Central

63. Cheng, Y, Li, S, Gao, L, Zhi, K, Ren, W. The molecular basis and therapeutic aspects of cisplatin resistance in oral squamous cell carcinoma. Front Oncol 2021;11:761379. https://doi.org/10.3389/fonc.2021.761379.Search in Google Scholar PubMed PubMed Central

64. Izzedine, H. Drug nephrotoxicity. Nephrol Ther 2018;14:127–34. https://doi.org/10.1016/j.nephro.2017.06.006.Search in Google Scholar PubMed

65. Attieh, RM, Nunez, B, Copeland-Halperin, RS, Jhaveri, KD. Cardiorenal impact of anti-cancer agents: the intersection of onco-nephrology and cardio-oncology. Cardiorenal Med 2024;14:281–93. https://doi.org/10.1159/000539075.Search in Google Scholar PubMed

66. Tan, WJT, Vlajkovic, SM. Molecular characteristics of cisplatin-induced ototoxicity and therapeutic interventions. Int J Mol Sci 2023;24:16545. https://doi.org/10.3390/ijms242216545.Search in Google Scholar PubMed PubMed Central

67. Tonnus, W, Maremonti, F, Belavgeni, A, Latk, M, Kusunoki, Y, Brucker, A, et al.. Gasdermin D-deficient mice are hypersensitive to acute kidney injury. Cell Death Dis 2022;13:792. https://doi.org/10.1038/s41419-022-05230-9.Search in Google Scholar PubMed PubMed Central

68. Zheng, ZL, Ma, JW, Luo, Y, Liang, GJ, Lei, SJ, Yan, KJ, et al.. Mechanism of dexmedetomidine protection against cisplatin induced acute kidney injury in rats. Ren Fail 2024;46:2337287. https://doi.org/10.1080/0886022x.2024.2337287.Search in Google Scholar PubMed PubMed Central

69. Zhu, B, He, J, Ye, X, Pei, X, Bai, Y, Gao, F, et al.. Role of cisplatin in inducing acute kidney injury and pyroptosis in mice via the exosome miR-122/ELAVL1 regulatory Axis. Physiol Res 2023;72:753–65. https://doi.org/10.33549/physiolres.935129.Search in Google Scholar PubMed PubMed Central

70. Wan, Y, Yu, Y, Yu, C, Luo, J, Wen, S, Shen, L, et al.. Human umbilical cord mesenchymal stem cell exosomes alleviate acute kidney injury by inhibiting pyroptosis in rats and NRK-52E cells. Ren Fail 2023;45:2221138. https://doi.org/10.1080/0886022x.2023.2221138.Search in Google Scholar PubMed PubMed Central

71. Xia, W, Li, Y, Wu, M, Jin, Q, Wang, Q, Li, S, et al.. Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation. Cell Death Dis 2021;12:139. https://doi.org/10.1038/s41419-021-03431-2.Search in Google Scholar PubMed PubMed Central

72. Shen, X, Wang, H, Weng, C, Jiang, H, Chen, J. Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. Cell Death Dis 2021;12:186. https://doi.org/10.1038/s41419-021-03458-5.Search in Google Scholar PubMed PubMed Central

73. Xu, J, Zhang, B, Chu, Z, Jiang, F, Han, J. Wogonin alleviates cisplatin-induced cardiotoxicity in mice via inhibiting gasdermin D-mediated pyroptosis. J Cardiovasc Pharmacol 2021;78:597–603. https://doi.org/10.1097/fjc.0000000000001085.Search in Google Scholar

74. Li, Y, Xia, W, Wu, M, Yin, J, Wang, Q, Li, S, et al.. Activation of GSDMD contributes to acute kidney injury induced by cisplatin. Am J Physiol Ren Physiol 2020;318:F96–106. https://doi.org/10.1152/ajprenal.00351.2019.Search in Google Scholar PubMed

75. Jiang, S, Zhang, H, Li, X, Yi, B, Huang, L, Hu, Z, et al.. Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. J Steroid Biochem Mol Biol 2021;206:105789. https://doi.org/10.1016/j.jsbmb.2020.105789.Search in Google Scholar PubMed

76. Pabla, N, Dong, Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008;73:994–1007. https://doi.org/10.1038/sj.ki.5002786.Search in Google Scholar PubMed

77. Tang, C, Livingston, MJ, Safirstein, R, Dong, Z. Cisplatin nephrotoxicity: new insights and therapeutic implications. Nat Rev Nephrol 2023;19:53–72. https://doi.org/10.1038/s41581-022-00631-7.Search in Google Scholar PubMed

78. Volarevic, V, Djokovic, B, Jankovic, MG, Harrell, CR, Fellabaum, C, Djonov, V, et al.. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 2019;26:25. https://doi.org/10.1186/s12929-019-0518-9.Search in Google Scholar PubMed PubMed Central

79. Gentilin, E, Simoni, E, Candito, M, Cazzador, D, Astolfi, L. Cisplatin-induced ototoxicity: updates on molecular targets. Trends Mol Med 2019;25:1123–32. https://doi.org/10.1016/j.molmed.2019.08.002.Search in Google Scholar PubMed

80. Rybak, LP, Mukherjea, D, Ramkumar, V. Mechanisms of cisplatin-induced ototoxicity and prevention. Semin Hear 2019;40:197–204. https://doi.org/10.1055/s-0039-1684048.Search in Google Scholar PubMed PubMed Central

81. Thomas, JP, Lautermann, J, Liedert, B, Seiler, F, Thomale, J. High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity. Mol Pharmacol 2006;70:23–9. https://doi.org/10.1124/mol.106.022244.Search in Google Scholar PubMed

82. Li, H, Song, Y, He, Z, Chen, X, Wu, X, Li, X, et al.. Meclofenamic acid reduces reactive oxygen species accumulation and apoptosis, inhibits excessive autophagy, and protects hair cell-like HEI-OC1 cells from cisplatin-induced damage. Front Cell Neurosci 2018;12:139. https://doi.org/10.3389/fncel.2018.00139.Search in Google Scholar PubMed PubMed Central

83. Fu, X, Wan, P, Li, P, Wang, J, Guo, S, Zhang, Y, et al.. Mechanism and prevention of ototoxicity induced by aminoglycosides. Front Cell Neurosci 2021;15:692762. https://doi.org/10.3389/fncel.2021.692762.Search in Google Scholar PubMed PubMed Central

84. Jiang, HY, Yang, Y, Zhang, YY, Xie, Z, Zhao, XY, Sun, Y, et al.. The dual role of poly(ADP-ribose) polymerase-1 in modulating parthanatos and autophagy under oxidative stress in rat cochlear marginal cells of the stria vascularis. Redox Biol 2018;14:361–70. https://doi.org/10.1016/j.redox.2017.10.002.Search in Google Scholar PubMed PubMed Central

85. de Jongh, FE, van Veen, RN, Veltman, SJ, de Wit, R, van der Burg, ME, van den Bent, MJ, et al.. Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 2003;88:1199–206. https://doi.org/10.1038/sj.bjc.6600884.Search in Google Scholar PubMed PubMed Central

86. Ma, H, Jones, KR, Guo, R, Xu, P, Shen, Y, Ren, J. Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. Clin Exp Pharmacol Physiol 2010;37:460–5. https://doi.org/10.1111/j.1440-1681.2009.05323.x.Search in Google Scholar PubMed

87. Qi, Y, Ying, Y, Zou, J, Fang, Q, Yuan, X, Cao, Y, et al.. Kaempferol attenuated cisplatin-induced cardiac injury via inhibiting STING/NF-κB-mediated inflammation. Am J Transl Res 2020;12:8007–18.Search in Google Scholar

88. Frank, D, Vince, JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ 2019;26:99–114. https://doi.org/10.1038/s41418-018-0212-6.Search in Google Scholar PubMed PubMed Central

89. Zhao, P, Wang, M, Chen, M, Chen, Z, Peng, X, Zhou, F, et al.. Programming cell pyroptosis with biomimetic nanoparticles for solid tumor immunotherapy. Biomaterials 2020;254:120142. https://doi.org/10.1016/j.biomaterials.2020.120142.Search in Google Scholar PubMed

90. Tan, Y, Chen, Q, Li, X, Zeng, Z, Xiong, W, Li, G, et al.. Pyroptosis: a new paradigm of cell death for fighting against cancer. J Exp Clin Cancer Res 2021;40:153. https://doi.org/10.1186/s13046-021-01959-x.Search in Google Scholar PubMed PubMed Central

91. Katopodis, P, Dong, Q, Halai, H, Fratila, CI, Polychronis, A, Anikin, V, et al.. In silico and in vitro analysis of lncRNA XIST reveals a panel of possible lung cancer regulators and a five-gene diagnostic signature. Cancers 2020;12:3499. https://doi.org/10.3390/cancers12123499.Search in Google Scholar PubMed PubMed Central

Received: 2024-03-23

Accepted: 2024-07-18

Published Online: 2024-08-09

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/oncologie-2024-0132

Keywords for this article

cancer treatment; cisplatin; pyroptosis; Garsdermin protein

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