Can artesunate be used as a repurposed drug for cancer treatment?

Artesunate as a Repurposed Drug for Cancer

Artesunate shows promising preclinical and early clinical anticancer activity, but it remains investigational and should not be used outside of clinical trials for cancer treatment, as no major oncology guidelines currently recommend it for this indication.

Current Evidence Status

Lack of Guideline Support

• No established oncology guidelines from major societies (NCCN, WHO, ASCO, ESMO) recommend artesunate for cancer treatment 1, 2
• The available guidelines focus exclusively on artesunate's role in malaria treatment, where it is the first-line therapy for severe malaria 3, 2

Preclinical and Mechanistic Evidence

The research literature demonstrates multiple anticancer mechanisms:

• Mechanisms of action: Artesunate induces apoptosis and autophagy in tumor cells, modulates the tumor microenvironment, regulates immune responses, overcomes drug resistance, and inhibits proliferation, migration, invasion, and angiogenesis 4
• Tumor types studied: Preclinical evidence exists for activity against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, melanoma, oral squamous cell carcinoma, bladder cancer, and prostate cancer 4, 5
• Mechanism specificity: The drug generates cytotoxic carbon-centered free radicals in the presence of free iron, with selectivity correlating to transferrin receptor 1 (TfR1) expression 6

Clinical Trial Data

Phase I Safety Study (Metastatic Breast Cancer)

• A 2017 prospective open-label phase I trial tested oral artesunate as add-on therapy in 23 patients with metastatic breast cancer 7
• Doses tested: 100,150, and 200 mg daily for 4 weeks 7
• Safety profile: Up to 200 mg/day (2.2-3.9 mg/kg/day) was safe and well tolerated, with only 3 patients experiencing 6 dose-limiting adverse events (leucopenia, neutropenia, asthenia, anemia) possibly related to artesunate 7
• The study recommended 200 mg/day for phase II/III trials with monitoring of reticulocytes, NTproBNP, audiological and neurological parameters 7

Renal Cell Carcinoma Studies

• In vitro and xenograft studies demonstrated that artesunate inhibited growth, metastasis, and angiogenesis in renal cell carcinoma models 6
• TfR1 upregulation correlated with distant metastasis and poor prognosis in clear cell RCC patients (n=469 TCGA dataset, n=119 tissue microarray) 6
• Artesunate sensitized RCC cells to sorafenib and induced G2/M cell cycle arrest and oncosis-like cell death 6

Colorectal Cancer Trial

• A completed randomized blinded trial in colorectal cancer showed perioperative artesunate reduced disease recurrence rates 8
• The Neo-Art trial, a larger Phase II RCT, is ongoing to confirm this effect 8

Critical Limitations

Absence of Phase III Data

• No completed phase III randomized controlled trials demonstrate survival benefit or quality of life improvement in any cancer type 4, 7, 5, 8
• The highest quality evidence is limited to phase I safety data and preclinical models 7, 6

Known Safety Concerns from Malaria Use

When considering potential cancer applications, clinicians must be aware of artesunate's known adverse effects:

• Post-artesunate delayed hemolysis (PADH): Occurs in approximately 37.4% of patients treated for severe malaria, requiring monitoring of hemoglobin, haptoglobin, and lactate dehydrogenase at days 7,14,21, and 28 9
• G6PD deficiency: Artesunate is not contraindicated but requires caution due to hemolysis risk 9
• Cardiac effects: Should be used with caution in patients at risk for QT interval prolongation 9
• Pregnancy: While approved for malaria in all trimesters, cancer treatment implications are unknown 9

Clinical Recommendation

For patients seeking artesunate for cancer treatment:

1. Enrollment in clinical trials is the only appropriate pathway for accessing artesunate for cancer, as efficacy and optimal dosing remain unestablished 7, 8

2. Standard-of-care cancer therapies should not be delayed or replaced with artesunate, given the lack of survival data and guideline support 1

3. If considering off-label use in refractory cases (which is not recommended), the phase I data suggests 200 mg/day oral dosing with intensive monitoring for hematologic toxicity, cardiac function, and neurological/audiological changes 7

4. Baseline and serial monitoring would need to include: complete blood count with reticulocytes, NTproBNP, hemoglobin/haptoglobin/LDH (for hemolysis), audiometry, and neurological examination 9, 7

Common Pitfalls to Avoid

• Do not substitute artesunate for proven cancer therapies: The preclinical promise has not translated to demonstrated clinical benefit 4, 5
• Do not assume malaria dosing applies to cancer: Chronic dosing for cancer differs substantially from short-term malaria treatment 3, 7
• Do not overlook hemolysis risk: PADH monitoring protocols from malaria treatment should be adapted for any cancer use 9
• Do not ignore drug-drug interactions: While not extensively studied in cancer contexts, artesunate metabolism may interact with chemotherapy agents 1