How Cisplatin Fights Cancer: DNA Damage and Metabolic Starvation

The Accidental Wonder Drug

In what can only be described as a scientific serendipity, Michigan State University researcher Barnett Rosenberg made an unexpected discovery in 1965 that would forever change cancer treatment. While studying how electricity affects bacterial growth, Rosenberg noticed that bacteria near platinum electrodes stopped dividing. This observation had nothing to do with cancer initially, but it ultimately led to the development of cisplatin, one of the most effective chemotherapy drugs ever created ⁷ .

For decades, scientists believed they understood how cisplatin worked: it damages cancer cell DNA, preventing replication and triggering cell death. However, recent research has revealed a surprising second mechanism that makes this drug even more fascinating—it literally starves cancer cells by cutting off their energy supply ^{1 6} .

Cancer's Sweet Tooth: The Warburg Effect

To understand cisplatin's newly discovered mechanism, we first need to discuss cancer's unusual eating habits. Unlike healthy cells that efficiently convert glucose into energy using oxygen, cancer cells behave differently. Even when oxygen is plentiful, they prefer to gorge on glucose and ferment it through a process called glycolysis, producing lactate as a byproduct. This phenomenon, known as the Warburg effect, seems counterintuitive at first glance.

Why would cancer cells choose this inefficient metabolic pathway? The answer lies in their need for speed and building materials. Glycolysis provides:

This metabolic reprogramming gives cancer cells a growth advantage, but it also creates a potential Achilles' heel—their dependence on glycolysis for survival and proliferation. Researchers have long wondered whether targeting this metabolic addiction could be the key to more effective cancer therapies.

Integrin β5: The Metabolic Master Regulator

Enter integrin β5 (ITGB5), a protein that sits on the surface of cells and acts as a communication hub between the cell and its environment. Integrins are like cellular antennae, detecting signals from the surrounding tissue and relaying them inside the cell to dictate behavior.

While integrins have traditionally been studied for their role in cell adhesion and migration, recent research has revealed that ITGB5 plays a special role in cancer metabolism, particularly in aggressive forms like triple-negative breast cancer and cervical cancer ⁴ . Think of ITGB5 as a metabolic switch that, when flipped on, turbocharges the cancer cell's glucose consumption.

ITGB5 doesn't work alone—it activates a downstream signaling pathway involving focal adhesion kinase (FAK), which in turn increases the production of proteins responsible for importing and processing glucose ¹ . This creates a perfect environment for cancer growth:

• Enhanced glucose uptake through increased glucose transporters (GLUT1 and GLUT4)
• Optimized glucose processing through lactate dehydrogenase B (LDHB)
• Continuous proliferation signaling through maintained FAK activation

In many cancers, especially aggressive forms, ITGB5 becomes overactive, essentially keeping the metabolic switch permanently flipped on and driving uncontrolled growth.

The Pivotal Experiment: Connecting the Dots

When researchers noticed that cancer cells consumed less energy after cisplatin treatment, they designed a series of elegant experiments to understand why. The central question was simple yet profound: Could cisplatin's effectiveness be due not only to DNA damage but also to metabolic disruption?

Step-by-Step Experimental Approach

The research team, whose work was published in the American Journal of Cancer Research, designed a comprehensive study to unravel this mystery ^{1 6} :

Revealing Results: Cisplatin's Metabolic Masterstroke

The experiments yielded clear and compelling evidence that cisplatin directly targets cancer metabolism through the ITGB5/FAK pathway.

Cisplatin's Impact on Cancer Glycolysis

When researchers measured glycolysis after cisplatin treatment, they found dramatic reductions in both glucose consumption and lactate production across both cancer types. This indicated that cisplatin was directly interfering with the cancer cells' ability to process glucose ^{1 6} .

At the molecular level, the changes were equally striking. Cisplatin treatment caused:

The most compelling evidence came from the genetic manipulation experiments. When researchers artificially increased ITGB5 levels in cancer cells, something remarkable happened—the cells became resistant to cisplatin's effects. The ITGB5-overexpressing cells maintained their glycolytic activity and continued proliferating despite cisplatin treatment ¹ .

ITGB5 Overexpression Reverses Cisplatin's Effects

The animal studies confirmed these findings in living systems. Tumors with normal ITGB5 levels shrank significantly with cisplatin treatment, while those with artificially high ITGB5 continued growing, demonstrating that ITGB5 levels directly influence cisplatin sensitivity ¹ .

The Scientist's Toolkit

These tools allowed researchers to systematically dissect the relationship between cisplatin, ITGB5, and cancer metabolism, providing multiple lines of evidence to support their conclusions.

Beyond Chemotherapy: New Therapeutic Horizons

The discovery of cisplatin's metabolic effects through ITGB5 inhibition opens exciting new possibilities for cancer treatment. Rather than relying solely on traditional chemotherapy, researchers can now explore combination therapies that simultaneously target DNA and cancer metabolism.

Promising Therapeutic Strategies

The revelation of cisplatin's dual mechanisms—damaging DNA while simultaneously starving cancer cells of energy—represents a major advancement in our understanding of cancer biology. It demonstrates that sometimes, the most effective solutions come from addressing multiple vulnerabilities at once.

For further reading on this topic, the original research study can be found in the American Journal of Cancer Research (2016), and background on cisplatin's discovery is available through Michigan State University archives ^{1 7} .