The main cause of failure in chemotherapy treatments is that tumors often develop resistance to anticancer drugs. A new study suggests that vitamin D may help overcome this challenge.

 

Researchers from South Dakota State University in Brookings have shown that calcitriol and calcipotriol — two active forms of vitamin D — can block a mechanism that allows cancer cells to become resistant to chemotherapy drugs.

 

This mechanism involves a drug transporter protein known as multidrug resistance-associated protein 1 (MRP1). The protein sits in the cell membrane and operates a pump that pushes anticancer drugs out of the cell.

 

The researchers discovered that calcitriol and calcipotriol can selectively target cancer cells that produce excessive amounts of MRP1 and destroy them.

 

Surtaj Hussain Iram, Ph.D., an assistant professor of chemistry and biochemistry at South Dakota State University, is the senior author of the study, which appears in the journal Drug Metabolism and Disposition.

 

Iram explains that several epidemiological and preclinical studies have already demonstrated the positive effects of vitamin D in reducing cancer risk and slowing disease progression.

 

However, this study is the first to show how vitamin D interacts with a drug transporter protein and selectively kills cancer cells that have become resistant to chemotherapy.

 

Iram notes that calcitriol and calcipotriol cannot destroy “naive” cancer cells — cells that have not yet developed resistance to chemotherapy. However, once cancer cells become drug-resistant, they become vulnerable to these vitamin D compounds.

 

Drug transporter proteins play an important role in controlling how drugs are absorbed, distributed, and expelled from cells in the body.

 

Cancer cells that become resistant to chemotherapy often produce excessive amounts of these transporter proteins. This overproduction is one of the main reasons chemotherapy drugs lose their effectiveness.

 

Previous research has linked the overexpression of MRP1 to multidrug resistance in several cancers, including breast, lung, and prostate cancer.

 

The ability of calcitriol and calcipotriol to kill chemotherapy-resistant cancer cells is an example of a phenomenon known as “collateral sensitivity.”

 

Collateral sensitivity refers to the ability of certain compounds to destroy multidrug-resistant cancer cells while leaving the original, non-resistant cells unaffected.

 

Approximately 90% of chemotherapy treatment failures occur because cancer cells acquire drug resistance. Multidrug-resistant cells can become resistant to medications that differ not only in structure but also in their mechanism of action.

 

One of the primary causes of this resistance is the activity of efflux pumps. These pumps remove chemotherapy drugs from cancer cells so efficiently that the remaining drug levels inside the cells are too low to be effective.

 

However, while the overproduction of MRP1 gives cancer cells the ability to expel chemotherapy drugs, it also creates a potential weakness. By targeting this protein, researchers can disable the pump that removes the drugs.

 

As Iram explains, gaining strength in one area often creates vulnerability in another. In nature, every advantage tends to come at a cost.

 

“Our approach,” he says, “is to target the Achilles’ heel of drug-resistant cancer cells by exploiting the fitness cost of resistance.”

 

Using cultured cancer cells, the research team tested eight compounds that previous studies had suggested could interact with the MRP1 protein.

 

Among these compounds, they found that calcitriol — the active metabolite of vitamin D3 — and its analog calcipotriol both blocked the transport function of MRP1.

 

These compounds also specifically destroyed cancer cells that overproduced the transporter protein.

 

The researchers conclude that calcitriol and its related compounds may have a potential role in targeting cancers in which MRP1 contributes to multidrug resistance.

 

Iram notes that the findings may also have implications for treating many other diseases.

 

MRP1 does not only reduce the effectiveness of cancer drugs. It can also weaken the impact of antibiotics, antiviral medications, anti-inflammatory drugs, antidepressants, and treatments used for HIV.

 

In addition, MRP1 belongs to a much larger family of transporter proteins known as ABC transporters, which move substances in and out of cells.

 

These transporters exist not only in animals but also in plants. In fact, plants contain an even greater number of ABC transporter proteins.

 

Because of this, the findings could have important implications for fields such as agriculture and food production.

 

“If we can better understand these transporters, we can improve drug efficacy,” Iram explains. “Patients may be able to take lower doses of medication while achieving the same therapeutic effect because the drugs will not be pumped out of cells as easily.”