Hydroxychloroquine (HCQ) is a medication used for malaria and autoimmune conditions like lupus and rheumatoid arthritis. Because of its influence on fundamental cellular functions, the drug has captured the interest of oncologists. Researchers are investigating whether its interactions within cells could be repurposed to treat cancer, leading to studies exploring its potential in this context.
Proposed Mechanism in Cancer Therapy
The reason for investigating hydroxychloroquine in cancer treatment is its ability to interfere with a cellular process called autophagy. Autophagy acts as a housekeeping system within a cell, breaking down and recycling old or damaged components like misfolded proteins and worn-out organelles. This process allows healthy cells to maintain internal balance and survive periods of stress.
Cancer cells, which often grow under stressful conditions, can hijack this recycling pathway. They use autophagy to endure the tumor’s harsh environment and survive stress from treatments like chemotherapy and radiation. This contributes to therapy resistance, where treatments become less effective over time.
Hydroxychloroquine is believed to disrupt this process by acting as an autophagy inhibitor. It is a lysosomotropic agent, meaning it accumulates inside lysosomes, the cell’s waste disposal and recycling centers. By raising the pH within the lysosomes, HCQ prevents them from fusing with autophagosomes—the vesicles that transport cellular waste—which halts the final step of the autophagic process. This blockage prevents the breakdown and recycling of cellular components, depriving the cancer cell of raw materials it needs to survive and making it more vulnerable to other cancer therapies.
Cancers Studied with Hydroxychloroquine
Research into hydroxychloroquine’s potential has focused on cancers known to depend on autophagy for their growth and survival. One of the most studied is glioblastoma, an aggressive form of brain cancer. Its reliance on autophagy to resist therapy makes it a logical candidate for testing autophagy inhibitors.
Other malignancies investigated include pancreatic cancer, known for its resistance to conventional treatments. Preclinical models suggest blocking autophagy could make pancreatic cancer cells more susceptible to chemotherapy. Melanoma and renal cell carcinoma have also been studied, often in combination with targeted therapies, to see if inhibiting autophagy can overcome resistance. The common thread is their high level of autophagy, which may be a vulnerability.
Current State of Clinical Research
Despite promising preclinical data, hydroxychloroquine is not an approved or standard treatment for any type of cancer. Its role is being evaluated strictly within clinical trials as an adjunct to established treatments, not as a standalone therapy. The goal is to determine if adding HCQ can sensitize cancer cells to chemotherapy, radiation, or targeted drugs, thereby improving outcomes for patients. So far, the results from these clinical trials have been mixed and have not shown a consistent effect.
Early-phase trials have explored the safety and dosing of HCQ when combined with cancer drugs. Some studies have shown modest benefits in small patient groups. For instance, a meta-analysis pointed to potential improvements for patients with glioblastoma and non-Hodgkin lymphoma when HCQ was added to standard therapy. However, it did not find significant benefits for non-small cell lung cancer or breast cancer.
Other studies have produced less encouraging results. A phase 2 trial using HCQ as a monotherapy for previously treated metastatic pancreatic cancer did not show significant clinical activity. Similarly, a study combining HCQ with the chemotherapy drug bortezomib in multiple myeloma patients found the combination was safe but did not clearly link autophagy inhibition with clinical response. More research, particularly randomized controlled trials, is needed to define if and how HCQ can be effectively integrated into cancer care.
Potential Side Effects in Oncology Use
While hydroxychloroquine is often well-tolerated for autoimmune diseases, its use in cancer patients, who may be more frail or receiving other potent medications, requires careful consideration of its side effects. The risks associated with the drug are a significant factor in clinical trials. Patients in trials are rigorously monitored to manage these potential complications.
A serious concern is retinal toxicity, which can damage the retina and lead to vision problems, necessitating regular ophthalmologic exams for patients in trials. Another area of concern is cardiotoxicity, including the potential for cardiomyopathy (damage to the heart muscle) and QT prolongation, an issue with the heart’s electrical rhythm that can increase the risk of dangerous arrhythmias.
Other reported side effects include low blood sugar (hypoglycemia), muscle weakness, and skin reactions. Because cancer patients are often already dealing with side effects from their primary treatments, the addition of HCQ can complicate their management. These potential harms underscore why the drug’s use in oncology remains strictly investigational and confined to controlled clinical settings.