Acute myeloid leukemia (AML) is an aggressive cancer of the blood and bone marrow that affects thousands of people worldwide. Traditional treatments often come with severe side effects, especially for older patients. However, the article discusses how pioglitazone, a medication commonly used to treat type 2 diabetes may one day be used in AML patients, explaining the science in simple terms and highlighting the significance of this discovery.

Understanding AML and the Need for New Treatments

AML is characterized by the rapid growth of abnormal white blood cells(leukocytes), which interfere with normal blood cell production. Symptoms can include fatigue, frequent infections, and easy bruising or bleeding. Standard treatments involve intensive chemotherapy, which isn’t suitable for everyone due to its toxicity.

There’s an urgent need for therapies that are both effective and have fewer side effects. Researchers are exploring medications that can selectively target cancer cells without harming healthy ones, improving patient outcomes and quality of life.

Introducing Pioglitazone: More Than a Diabetes Drug

Pioglitazone is a medication from the thiazolidinedione class, primarily prescribed to manage blood sugar levels in type 2 diabetes patients. It works by activating a protein in the body called peroxisome proliferator-activated receptor gamma (PPARγ). This activation improves insulin sensitivity, helping control glucose levels.

But here’s where it gets interesting: PPARγ also plays a role in regulating cell growth and death, making it a potential target in cancer treatment. Scientists wondered if pioglitazone could influence cancer cells the same way it affects cells involved in diabetes.

The Study: Investigating Pioglitazone’s Effect on AML

A group of researchers set out to explore whether pioglitazone could be beneficial for AML patients. They focused on two main objectives:

1. Measuring PPARγ and PTEN Levels in AML Patients: They compared the levels of PPARγ and a tumor-suppressor gene called PTEN in the blood samples of 30 AML patients and 10 healthy individuals.
2. Testing Pioglitazone on Leukemia Cells: They treated U937 leukemia cells (a type of AML cell line) with pioglitazone to observe its effects on cell survival and growth.

Key Findings Explained

Higher PPARγ Levels in AML Patients

• What They Found: AML patients had significantly higher levels of PPARγ compared to healthy individuals.
• What It Means: The increased PPARγ might be the body’s way of trying to combat the cancer cells. Since PPARγ can regulate cell death, higher levels could indicate that activating this pathway might suppress leukemia.

Lower PTEN Levels in AML Patients

• What They Found: PTEN levels were significantly lower in AML patients.
• What It Means: PTEN is a gene that helps control cell growth. Lower levels suggest that cancer cells are evading normal growth controls, contributing to leukemia progression.

Pioglitazone Reduces Leukemia Cell Survival

• What They Found: When U937 leukemia cells were treated with pioglitazone, their survival rate decreased significantly.
• Numbers to Know:
  • At a concentration of 250 µM, only about 3% of the leukemia cells remained metabolically active after 48 hours.
• What It Means: Pioglitazone effectively kills leukemia cells in a dose-dependent manner, meaning higher doses lead to more cell death.

Induction of Cell Cycle Arrest and Apoptosis

• What They Found: Pioglitazone caused leukemia cells to halt in the G1 phase of the cell cycle and induced apoptosis (programmed cell death).
• Numbers to Know:
  • The percentage of cells in the G1 phase increased from 36% (control group) to 80% after pioglitazone treatment.
  • The sub-G1 population (indicative of apoptosis) increased from 4.4% to 34.13%.
• What It Means: Pioglitazone not only stops leukemia cells from multiplying but also triggers them to die, which is crucial for eliminating cancer cells.

Interpreting the Biostatistics in Simple Terms

Understanding the numbers in medical studies can be daunting, but here’s a straightforward explanation:

• Significant Decrease in Cell Survival: When researchers mention a significant decrease to 3% cell activity, it means that out of 100 cancer cells, only 3 survived after treatment. This shows a strong effect of pioglitazone on killing cancer cells.
• Increase in Apoptosis Indicators: An increase from 4.4% to 34.13% in apoptotic cells indicates that pioglitazone causes many more cancer cells to die naturally, which is a desirable outcome in cancer treatment.
• Cell Cycle Arrest at G1 Phase: Increasing the G1 phase cell population to 80% means the majority of cancer cells are stuck in the phase where they can’t replicate DNA or divide, effectively halting tumor growth.

Background Context: The Science Behind PPARγ and PTEN

What is PPARγ?

PPARγ is a receptor found inside cells that, when activated, can influence genes controlling cell growth, fat storage, and insulin sensitivity. In cancer cells, activating PPARγ can lead to reduced proliferation and increased cell death.

Role of PTEN in Cancer

PTEN is a tumor suppressor gene that helps regulate cell division and survival. Loss or reduction of PTEN function can lead to uncontrolled cell growth, a hallmark of cancer.

Moving Forward: The Future of Pioglitazone in AML Treatment

While these findings are promising, more research is needed, including clinical trials with AML patients, to determine the safety and efficacy of pioglitazone in a real-world setting.

What Patients Should Know

• Consult Healthcare Providers: Patients should not self-medicate with pioglitazone for cancer treatment. Always consult oncologists or healthcare professionals for personalized medical advice.
• Hope for Better Treatments: This research represents a step toward more effective and less toxic treatments for AML, potentially improving survival rates and quality of life.

Human Trials to Back Up Theory

 In a randomized clinical trial, newly diagnosed AML patients were randomized to 1 of 2 groups. Patients in both groups received cytarabine (100 mg/m2 per day for 7 days) and daunorubicin (60 mg/m2 per day for 3 days). Patients in the pioglitazone group additionally received oral pioglitazone (45 mg per day). The 2 groups were compared according to remission rate, laboratory findings, and adverse events during treatment. The size of each of the 2 groups was 20 individuals each.

Increased Complete Remission Rate: The complete remission (CR) rate was 50% in the pioglitazone group compared to 30% in the control group, showing a 20% higher remission rate. Although this difference was not statistically significant (P = .202), it may be clinically meaningful in a clinical setting. Despite not reaching statistical significance ,it is important to realize that it is extremely difficult to reach clinical significance with only 20 individuals in each treatment arm for a disease as complex as AML where there may be additional factors. It is worth noting that with a sample size of just 20, there is only an approximately 1 in 5 chance that the findings of the higher remission rate were due to chance alone.

Manageable Adverse Events: Pioglitazone did not lead to serious adverse events. It was discontinued in two patients due to elevated liver enzymes and myopathy, but these side effects were manageable and did not result in long-term complications.

Laboratory Findings:

Often, adding more medicines translates to more efficacy in treating medical conditions, potentially at the cost of causing additional side effects. The subsequent numbers for the liver and kidney demonstrate that Pioglitazone does not cause any meaningful damage or additional side effects.

• Serum Alanine Aminotransferase (ALT): In the fourth treatment week, the pioglitazone group had a mean ALT level of 65.5 mg/dL versus 33.6 mg/dL in the control group, a significant increase (P = .039).
• Serum Creatinine: Throughout all treatment phases, the pioglitazone group had significantly higher mean serum creatinine levels compared to the control group (P < .05). However, these increases did not lead to serious kidney complications.
• Other Parameters: No significant differences were observed between the two groups in other laboratory tests, including aspartate transaminase (AST), alkaline phosphatase (ALP), fasting blood sugar (FBS), white blood cell count, and platelet count.

Conclusion

Pioglitazone, is likely an excellent addition to a standard chemotherapy regimen for AML as it yields a better remission rate, and biological markers suggest fewer side effects. The lack of statistical significance should not be discouraging given the context of a small sample size and the numerous variants of AML. The increase in damage markers in the kidney and liver were not statistically significant,however, even if they were, the numbers presented above are clinically irrelevant.

Frequently Asked Questions (FAQs)

Is pioglitazone currently approved for treating AML?

No, pioglitazone is not currently approved for AML treatment. It’s approved for type 2 diabetes. Ongoing research explores its potential in cancer therapy; therefore, off-label use is decided individually.

Can I take pioglitazone if I have AML?

You should only take pioglitazone for AML with the guidance of an oncologist. It is reasonable to show the original research paper to the oncologist to add to the chemotherapy regimen. If the patient is a good candidate, for example, being free from cardiovascular issues, the physician will make a risk-benefit analysis.

What are the side effects of pioglitazone?

Some peripheral Edema is expected, which is typically not an issue unless the patient has heart failure. A licensed physician should be able to judge each patient’s circumstances.

Disclaimer: This article is for informational purposes only and does not substitute professional medical advice. Always consult a qualified healthcare provider for guidance tailored to your health situation.

At CanadianInsulin, we’re dedicated to providing up-to-date information and quality medications to support your health needs. Explore our range of GLP-1 receptor agonists and consult with our pharmacists for more information.