Article Summary
Pancreatic cancer, particularly a type known as pancreatic ductal adenocarcinoma (PDAC), is one of the deadliest forms of cancer, largely due to a mutation in a gene called KRAS that makes it resistant to current treatments like chemotherapy. Despite ongoing research, finding effective treatments for PDAC has been challenging. This article explores the potential of targeting the cancer’s metabolism—how it uses energy and nutrients to grow—through a process called ferroptosis, a type of cell death induced by iron accumulation in the cells. It discusses the use of a drug called Artesunate, traditionally used for malaria, and its promising ability to kill cancer cells by inducing ferroptosis. Additionally, it touches on the use of another drug, Cisplatin, in combination with current treatments to enhance their effectiveness. The piece highlights the importance of innovative approaches in cancer treatment, specifically targeting the metabolic pathways of cancer cells, offering hope for more effective therapies for PDAC.
Understanding Pancreatic Ductal Adenocarcinoma and Novel Treatment Approaches
Introduction to Pancreatic Ductal Adenocarcinoma (PDAC)
Amongst the most lethal cancers is pancreatic ductal adenocarcinoma [PDAC] (Luo,2021). PDAC accounts for 85 – 90 % of all pancreatic cancers (Luo, 2021; Orth et al., 2019). According to the Australian Institute of Health and Welfare [AIHW], PDAC was the third most common cancer to cause death in 2022, and the 5-year survival rate is just 12%. A unique hallmark of PDAC is the oncogenic mutation, Kirsten rat sarcoma [KRAS] (Luo, 2021). The KRAS oncogene is present in the deadliest of cancers (Wang, 2022). PDAC harbouring KRAS mutation is notorious for being undruggable and developing chemotherapy resistance (Luo, 2021) due to manipulating cancer cell metabolism, facilitating unrestricted growth (Pupo et al., 2019). KRAS-mutated cells hijack metabolic pathways to facilitate iron accumulation (Jiang et al., 2022), which fuels the cancer cell (Hsu et al., 2020). The standard treatment for PDAC is chemotherapy; this is given to reduce tumour size, not cure (Luo, 2021).
Although novel therapies have been designed to address cancers with the KRAS mutation, the results have been dismal (Huang et al., 2021). Current trials for therapies to treat PDAC with KRAS mutation will not conclude until 2027 (Australian New Zealand Clinical Trials Registry [ANZCTR]. The urgency of finding an effective treatment for PDAC is indisputable, and this paper introduces a novel, theoretical framework for the potential treatment of KRAS PDAC, intending to provide swift, evidence-based therapeutic options that are immediately available and approved for use.
Metabolic Theory
Current cancer research and drug formulation are built on the foundations of the somatic mutation theory [SMT], which describes cancer as arising from genetic mutations (Seyfried & Chinopoulous, 2021). Critics question the ability of the SMT to provide the basis for cancer research (Brucher & Jamal, 2016; Duesberg & Rasnick, 2000; Seyfried, 2012; Soto & Sonnenschen, 2004). Although KRAS mutation is an essential part of this paper, it is viewed from the perspective of its unique metabolic characteristics rather than being a genetic cause of cancer. Many researchers agree that genetic mutations occur only after mitochondrial damage, potentially causing genes to activate (Seyfried & Chinopoulous, 2021). The theory that cancer begins as a metabolic disorder within cells was first documented by Otto Warburg in 1956, and this theory has been the focus of recent research (Bragazzi & Sellami, 2020; Gyamfi et al., 2021; Seyfried & Chinopoulos, 2021). Metabolism is described as the biochemical pathways and processes within cells (Wilkins et al., 2021), and cancer cells show metabolism that differs from normal cells (Seyfried, 2012). Studies on cancer cell metabolism have sought to discover the unique characteristics of energy pathways and then hijack the metabolic process to deprive the cell of necessary fuel (Gyamfi et al., 2021).
Ferroptosis
Ferroptosis was first discovered in 2012 (Dixon et al., 2012), and it is a unique type of regulated cell death (Chen et al., 2023). The term ‘ferroptosis’ describes the process of cell death via iron-dependent pathways (Zhang et al., 2022). Once normal cells transform into cancer cells, they have the metabolic requirement for extra iron to proliferate (Pfeifhofer-Obermaie et al., 2018). Iron accumulation within cells can be taken advantage of when particular substances are given to trigger ferroptosis cell death (Dixon et al., 2012). Just as iron can induce ferroptosis (Chen et al., 2023), iron inhibitors such as deferoxamine can bring ferroptosis to a halt (Wu et al., 2019; Yan et al., 2021; Zilka et al., 2017), thus demonstrating that iron is an important, controllable, metabolic target for ferroptosis. Cancer death by ferroptosis is caused by the cell’s accumulation of reactive oxygen species [ROS], leading to cell death (Perilo et al., 2020; Toyokuni et al., 2017). Therefore, ferroptosis is an exciting option available as a novel approach to the treatment of KRAS-mutated PDAC (Andreani et al., 2022; Chen et al., 2021; Yang et al., 2021).
Artesunate Induces Ferroptosis
Artesunate [ART] is a derivative of Artemisia annua and has been used for decades to treat malaria (Khanal, 2021). ART has an excellent safety profile established from extensive pharmacokinetic studies (Kouakou et al., 2019; Zou et al., 2020). Evidence suggests that ART is effective against cancer cells (Ruwizhi et al., 2022; Yang et al., 2021). Du et al. (2010) were the first to identify pancreatic cancer cell death induced by ART in both in vitro and in vivo studies. These researchers found that ART induced cell death via a novel pathway they could not identify. In the same year, Youns et al. (2009) demonstrated ART’s anti-cancer effects and hypothesised that the tumour’s genetic makeup might determine ART’s effectiveness. The solid link between ART, ferroptosis, and the KRAS mutated pancreatic cell lines was first revealed by Eling et al. (2015). These researchers found that ART-induced ROS-dependent lethality in cell lines harbouring mutated KRAS genes. More recently in-vitro Wu et al. (2019) found that ART inhibited cell proliferation, invasion, and metastasis in pancreatic cell lines. Although much research has been based on the in vitro two-dimensional model, this application has significant limitations due to the absence of a tumour microenvironment (Kapalczynska et al., 2018).
It is widely understood that PDAC has a complex microenvironment (Truong & Pauklin, 2020), which consists of substances that create a considerable barrier around the tumour (Skorupun et al., 2021). The tumour microenvironment [TME] is essential in cancer research (Baghban et al., 2020). The TME, comprised of immune cells, blood vessels, stromal cells, and extracellular matrix (Anderson & Simon, 2020), is critical In facilitating tumour growth, metastasis, and drug resistance (Fontana et al., 2021). KRAS mutated cells crosstalk with the TME, altering their metabolic behaviour (Kawada et al., 2017). Therefore, using a model that includes the TME may foster more accurate cancer research (Atat et al., 2022). Niederreiteret et al. (2023) conducted research using three-dimensional [3D] models containing a TME to assess ART’s effect on cancer. In some cases, ART showed more lethality than chemotherapy; in others, it had no effect. No pancreatic cell model was used in this experiment, and no genetic mutation was identified in the cells. The results of this study were diverse and possibly indicated the unreliability of 3D modelling. This unreliability has been summarised by Antunes et al. (2022).
Although no human trials have been conducted using ART in patients with pancreatic cancer, the limited number of trials that have been done in other cancers yielded exciting results. One open-label trial with advanced cervical cancer patients given oral ART revealed remission in nine out of ten patients (Jansen et al., 2011). Interestingly, none of the subjects were undergoing concurrent oncological therapy. In the only randomised, placebo control trial documented (Krishna et al., 2015), the authors compared oral ART versus placebo in patients with colorectal cancer in the two weeks between diagnosis and resection. The patient group was small, ART n-9, placebo n-11. This study was interesting as colorectal cancers contain the KRAS mutation in 48% of cases (Zhu et al., 2021). Their primary endpoint of detection apoptosis was not met; however, only one patient in the ART group relapsed, compared to six in the placebo group. The most recent human trial was to test the response to intravaginal ART for intraepithelial cervical cancer (Trimble et al., 2020). This was an open-label trial with 28 participants. Histologic regression was observed in 69.9% of patients. Human trials involving ART have not been focused on a particular metabolic target, nor have they involved patients with PDAC with the KRAS mutation.
Case studies explore applying complex issues within a real-life setting, leading to new research questions (Sayre et al., 2017). Sing and Verma (2002) presented a case study on a 72-year-old gentleman with laryngeal carcinoma. They administered ART 60mg via intramuscular injection daily from day one to 15. Following that, oral ART was given at a dose of 50mg per day. The authors reported a 70% reduction in laryngeal tumour size after nine months of treatment. It is not indicated whether the patient was undergoing concomitant anti-cancer treatment. Berger (2005) treated two patients with metastatic melanoma patients with ART, reporting tumour regression in one patient and overcoming chemoresistance in the other. Michaelson (2015) used IV ART for prostate cancer, reporting a decrease in cancer markers, tumour regression, and several months symptom-free.
Cisplatin Induces Ferroptosis
FOLFURINOX or gemcitabine are the chemotherapeutics used to treat PDAC; however, they only extend survival by 4.41 months and 5.65 months, respectively (Gold & Raja, 2023). It would be helpful to consider chemotherapeutic drugs that have a metabolic effect. Cisplatin is a classical chemotherapy drug that has been used for decades, although its efficacy is limited due to the acquired drug resistance of tumours (Kasherman et al., 2009). Interestingly, cisplatin has been shown to induce ferroptosis in vitro (Guo et al., 2018). Other research has demonstrated cisplatin depletes the cellular antioxidant glutathione, and this process also triggers ferroptosis (Dixon et al., 2012; Raho et al., 2020; Sun et al., 2018), which makes cisplatin another potential metabolic therapy. The addition of cisplatin to gemcitabine increases the overall tumour response rate in pancreatic cancer by 48.2% (Ouyong et al., 2016).
Conclusion
Extensive research exists on ART and ferroptosis. The limitations are that most studies have been performed in vitro and do not truly reflect the complexity of cancer. The few case studies that have been presented give a real-world view of the effectiveness of ART. More extensive human clinical trials are needed to bridge the current knowledge gap. ART is a medicine that should taken under the guidance of a practitioner familiar with its potential interactions and side effects.
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