‘Pro version’ of cisplatin keeps its cancer-killing power while reducing side effects

Cisplatin is one of the most successful cancer medicines ever developed. Doctors use it to treat many cancers, including lung, ovarian, breast, testicular and head and neck cancers. However, cisplatin has a serious problem. It does not attack only cancer cells. It can also reach healthy organs and damage them. In particular, cisplatin can harm the kidneys and peripheral nerves. Patients receiving cisplatin often experience pain, tingling, numbness or weakness in their hands and feet. These side effects can become so severe that doctors must reduce the dose or stop treatment completely.

This led our research team to ask a simple question: Can we keep cisplatin’s cancer-fighting power while reducing its harmful side effects?

To explore this idea, we developed a new molecule called cisproplatin, or CPP. We can think of it as a smarter, “pro version” of cisplatin designed to remain stable while traveling through the body and become active under tumor-like conditions. The research is published in the Journal of Medicinal Chemistry.

Two medicines joined into one molecule

Cisproplatin combines two existing medicines in a single molecule. The first is cisplatin, the well-known cancer drug. The second is probenecid, a medicine traditionally used to treat gout. Probenecid can affect how foreign substances and medications are transported through the kidneys and may help cancer cells retain drugs.

However, simply giving cisplatin and probenecid together is not the same as joining them chemically on a single platform. When two separate medicines are injected, they travel through the body at different speeds and reach different organs, making it difficult for them to work in synergy.

We therefore attached probenecid directly to a modified form of cisplatin, creating one stable, platinum-containing molecule, cisproplatin.

Stays stable until it reaches the right conditions

Cisplatin is highly reactive. While this reactivity helps it damage cancer-cell DNA, it can also cause the drug to react prematurely with healthy tissues.

Cisproplatin acts like a package with a chemical safety lock. During circulation in the blood, the drug stays locked and stable, avoiding unwanted reactions with healthy tissues. Under laboratory conditions, cisproplatin remained largely intact for several days in blood-like conditions.

However, when cisproplatin encounters a “reducing” chemical environment, a condition typical of many cancer cells, that safety lock opens, releasing active cisplatin-like platinum species and probenecid right where they are needed.

Strong activity against many cancer types

Cisproplatin was tested through the U.S. National Cancer Institute’s Developmental Therapeutics Program, which evaluates new compounds against 60 human cancer cell lines.

Cisproplatin showed strong activity across a wide range of cancer cells, including cells from breast, melanoma, non-small cell lung, brain, leukemia, colon, kidney, prostate and ovarian cancers, often outperforming standard cisplatin.

We also evaluated cisproplatin in two mammalian cell lines of triple-negative breast cancer. These are aggressive types of breast cancer that do not have the three receptors commonly targeted by several breast cancer medicines.

In one cell line, cisproplatin was active at approximately 0.128 micromolar, whereas cisplatin required significantly higher concentrations to achieve a similar effect. Cisproplatin also slowed the cells’ ability to migrate and form new colonies. These results suggest that cisproplatin affected both short-term survival and long-term cancer-cell growth.

An unusual two-step DNA attack

We originally expected cisproplatin to act mainly as a protected carrier that would release cisplatin after activation. However, we found something unique. The intact cisproplatin molecule appeared to have cancer-fighting activity even before it fully released cisplatin.

DNA is often visualized as a twisted ladder. Cisplatin works by attaching to this ladder and creating chemical links that prevent the cell from copying its DNA.

Our experiments suggested that intact cisproplatin can first nestle between parts of the DNA structure or fit into one of its narrow grooves. These are noncovalent interactions, meaning cisproplatin can associate with DNA without immediately making the same permanent chemical bonds formed by cisplatin.

Later, after cisproplatin is reduced, it can release cisplatin-like platinum species that form stronger chemical links with DNA.

This two-step behavior helps explain why cisproplatin demonstrated such strong potency across diverse cancer-cell types.

Less kidney and nerve damage and higher blood circulation in mice

A powerful cancer medicine is useful only when the body can tolerate it. When we compared cisproplatin and cisplatin in mice, the differences were striking.

Mice treated with standard cisplatin suffered severe toxicity, including weight loss, poor grooming, abnormal posture and nerve-fiber damage in their sciatic nerves, mirroring the painful peripheral nerve damage seen in human patients.

In contrast, mice treated with cisproplatin tolerated higher doses, maintained better health and showed far fewer behavioral or structural signs of nerve damage. Furthermore, cisproplatin circulated in the blood longer, with a half-life of approximately 8.5 hours compared with approximately 3.85 hours for cisplatin, and accumulated significantly less platinum in the kidneys, suggesting lower nephrotoxicity.

What this discovery means and what it does not mean

While these results are encouraging, cisproplatin is still an experimental compound and is not yet ready for human patients. Our findings come from laboratory cell lines and preliminary mouse models. The next major steps involve testing whether cisproplatin can effectively shrink tumors in complex animal models, followed by detailed studies on its metabolism, optimal dosing and long-term safety before clinical trials can be considered.

Nevertheless, this research demonstrates that classic chemotherapy drugs can be redesigned in a smarter way. Cisproplatin offers a promising blueprint for separating a drug’s cancer-killing potency from its life-disrupting side effects.

This story is part of Science X Dialog, where researchers can report findings from their published research articles. Visit this page for information about Science X Dialog and how to participate.

Who’s behind this story?

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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Kajol is a final-year Ph.D. student in the Department of Biological Sciences at the Indian Institute of Science Education and Research (IISER) Berhampur. Her research focuses on developing targeted molecular therapies that reduce side effects while maintaining the effectiveness of both traditional and novel cancer drugs.

Dr. Rakesh Kumar Pathak is an Associate Professor in the Department of Chemical Sciences at IISER Berhampur, India, where he leads the Laboratory of Medicinal Inorganic Chemistry and Nanomedicine. Trained at IIT Bombay, the University of Georgia, Ohio State University, and Vanderbilt University, his research integrates synthetic chemistry, medicinal inorganic chemistry, biology, and nanotechnology.

AI-assisted tools were used for language refinement and preliminary figure conceptualization. All scientific content, interpretation, and final figure preparation were reviewed and approved by the authors.