The Lifesaving Hunch: How Rosenberg’s Unexpected Discovery of Cisplatin Changed Medicine

Ah, cisplatin: the first metal-based anticancer drug ever approved for treatment. Also, the cornerstone of my early research career. I still recall when I relocated to Cardiff, UK. It was back in February 2003—cold, lonely, lost. A whole lifetime ago. Back then, my English was far from perfect, and during my first meeting with the man who was to become my PhD supervisor, I barely grasped a word. He was outlining what my computational chemistry research would encompass, and there I was, struggling to catch up. The objective for my PhD was ambitious: to simulate the activation of cisplatin and understand its impact on DNA. Of that time, filled with research, getting used to a new place, and making friends, one science story really sticks with me: how Rosenberg stumbled upon cisplatin’s discovery. It’s quite the story, honestly. Cisplatin went from being a lab anomaly to a big deal in cancer treatment. So, how did a small metal-based molecule become one of the world’s most administered anticancer drugs? Well, keep reading ’cause that’s exactly what we’re going to talk about today.

The Lifesaving Hunch: How Rosenberg's Unexpected Discovery of Cisplatin Changed Medicine | From Atoms To Words | Arturo Robertazzi
Iron shavings in a magnetic field – Animation Credit

Rosenberg’s hunch: Cisplatin, from anomaly to lifesaver

Can an electrical field stop cell division? Can electricity control life? In the dim corridors of Michigan State University, Dr. Barnett Rosenberg, a keen-eyed biophysics researcher, found himself standing at the crossroads of curiosity and scientific innovation. The year is 1965. With the deductive reasoning of a seasoned detective, he noticed something peculiar: the microscopic images of dividing cells bore an uncanny resemblance to the pattern of iron shavings in a magnetic field.

Fueling an elusive hunch, he wondered: Could an electrical field exert its influence over cell division?

Remember, we are in 1965. The Beatles are singing “Help!” and Soviet cosmonaut Alexei Leonov has conducted the first spacewalk. The discovery of Watson and Crick’s DNA is less than 12 years old.

Now, considering the times, Rosenberg’s hunch was downright extraordinary—an out-of-the-box hypothesis that cried out for testing; a mysterious phenomenon that held the promise of a breakthrough.

What followed was not just an experiment but a series of events that one could only describe as serendipitous detective work, ultimately culminating in an accidental discovery. And what a discovery it was!

To investigate the effect of an electric field on cellular division, Rosenberg and his team of scientific sleuths plunged platinum electrodes into cultures of E. coli bacteria and cranked up the voltage. They expected some sort of reaction, but nothing could have prepared them for what ensued.

As the electric current surged, Rosenberg made a stunning observation: the bacterial cells ceased their division, morphing up to 300 times their regular size. And yes, upon cutting the power, like clockwork, the cells resumed their division.

The effect was evident, but the cause?

It must be the electrical field, Rosenberg initially concluded. Just like the iron shavings, perhaps the electrical field was also able to control life?

But after relentless investigation and the ruling out of other possibilities, the true culprit emerged from the shadows. Rosenberg realized that the effect on cell division was not due to the electrical field, but to a small molecule formed from the platinum electrodes he had used.

That molecule was cisplatin.

This is the moment Rosenberg traded in his serendipity for a shot of genius.

If such a small molecule could interfere with cell division, he pondered, might it also interfere with the process when it leads to nefarious consequences? Could cisplatin defeat cancerous cells?

So, Rosenberg tested cisplatin on mice with sarcoma. The results were clear: although highly toxic at large doses, cisplatin effectively fought against tumors, significantly reducing their size.

Despite these results, the journey of cisplatin from a laboratory anomaly to a beacon of hope in oncology was fraught with skepticism. The wider cancer research community viewed the prospect of introducing heavy metals into the human body with apprehension. But Rosenberg found an ally in the National Cancer Institute, which, impressed by the compelling evidence, supported Rosenberg’s quest, funding research that would create waves in medical history.

It wasn’t until 1972 that the tides truly turned, with Lawrence Einhorn’s pivotal clinical trials. These trials yielded excellent results, particularly in patients tormented by testicular cancer, leading to the FDA’s historic approval of cisplatin as the first metal-based anticancer drug.

That triumph was nearly half a century ago. Countless studies, medical trials, and real-world applications have since followed. So, where does cisplatin stand in today’s battle against cancer? What’s its mechanism of action?

Further reading:
▸ Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode, Rosenberg 1965
▸ Cisplatin: The First Metal-Based Anticancer Drug – Ghosh 2019

Cartoon showing a cisplatin-DNA complex. Animation Credit

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From entering cells to fighting cancer: How does cisplatin work?

Years after its discovery, cisplatin continues to stand its ground as a pioneering force among chemotherapeutic agents. This formidable small molecule remains a staple in the treatment protocols for nearly half of all cancer patients. It’s a crucial weapon against a multitude of solid tumors.

Yet, the positive impact of cisplatin is shadowed by debilitating side effects. In response, the scientific community has rallied, devising strategic countermeasures: combination therapies. By pairing cisplatin with other drugs, researchers aim to outmaneuver the cancer cells, enhancing efficacy, and potentially dampening the drug’s harsher effects.

See, cisplatin does not discriminate; it is not selective towards cancer cells. Cisplatin’s mechanism is both brutal and elegant: a biochemical attack that inflicts DNA damage, disrupts cellular processes, and triggers a cascade leading to cancer cell death.

Now, let’s examine cisplatin’s mechanism of action, from when it enters the bloodstream to exerting its anticancer effect.

Further reading: Quantum Chemical Studies of DNA and metal-DNA structures, Robertazzi 2006

1. Reaching the Cell and Cisplatin Activation

Cisplatin is introduced into the bloodstream via intravenous injection. While a substantial portion is neutralized by plasma proteins, the remainder – between 5% and 35%, infiltrates (cancer) cells by diffusing through the plasma membrane, a process mediated by the presence of the copper transporter protein, CTR1.

Once inside the cell, cisplatin undergoes a critical transformation. One or two chloride ligands are replaced by water molecules. Cisplatin is now activated.

This shift, prompted by the cell’s low chloride concentration – basic old equilibrium chemistry – readies cisplatin for its interaction with the cell’s molecular components.

The Lifesaving Hunch: How Rosenberg's Unexpected Discovery of Cisplatin Changed Medicine | From Atoms To Words | Arturo Robertazzi

Molecular Mechanism of Cisplatin Activation. My personal journey with cisplatin began during my PhD research, with my first study focusing on its hydrolysis and activation. This was back in 2004, nearly 20 years ago! By using Density Functional Theory (DFT) calculations, I investigated the structures of hydrogen-bonded clusters formed between cisplatin and water. To dissect these structures, I employed a quantitative analysis based on electrostatic potentials and Atoms in Molecules Theory. My findings confirmed cisplatin’s versatility in hydrogen bonds, where it acts both as a donor and acceptor. I also explored how solvation influences the barriers to cisplatin’s hydrolysis. The activation energy calculated for cisplatin closely mirrored experimental data, showing a mere difference of 0.03 kcal/mol — now that’s chemical accuracy! Not too shabby for a first paper, right?
The animation shows a quantum nanoreactor simulation of the hydrolysis of cisplatin – simulated with QuantistryLab

2. Cisplatin binding the DNA

Cisplatin’s core mission begins as it interacts with DNA within the cell nucleus. Here, it binds preferentially to guanine bases, creating a range of DNA adducts.

These interactions disrupt the DNA’s normal architecture, introducing kinks and bends that inhibit essential processes like replication and transcription. Through this structural upheaval, cisplatin cripples the cell’s genetic instruction manual.

The Lifesaving Hunch: How Rosenberg's Unexpected Discovery of Cisplatin Changed Medicine | From Atoms To Words | Arturo Robertazzi

DFT Study of Cisplatin-DNA Bases Interactions. To explore how cisplatin binds to DNA, I built small DNA models and investigated their interaction with cisplatin using DFT and ab initio calculations. After making sure the calculations could accurately reproduce known experimental structures, I developed a method to decompose the total binding energy of cisplatin-DNA base complexes into covalent and hydrogen bond contributions. I observed that cisplatin’s preference for guanine is not solely due to hydrogen bonding, despite the formation of strong interactions, but also due to the metal (covalent) bond with the DNA bases. What I found particularly interesting was the effect on the Watson-Crick base pairing. While the total stability of platinated bases was hardly affected, I showed that a strong redistribution along the hydrogen bonds occurs that leads to a significant distortion of the standard base pairing and therefore of the DNA.
The figure illustrates cisplatin-DNA adducts. Adapted from Robertazzi 2006

3. Anticancer Effects

The molecular chaos caused by cisplatin is not without consequence. The cell marshals its DNA repair mechanisms, including the robust Nucleotide Excision Repair and Mismatch Repair systems, in a valiant effort to reverse the damage.

However, the severity of cisplatin’s modifications often proves insurmountable. Failed repair attempts send an unmistakable signal, triggering the process of programmed cell death.

It is through this orchestrated collapse of cancer cells from within that cisplatin asserts its cytotoxic effects, which, in the best cases, yield a lifesaving power, and in the worst, produce harsh side effects.

The Lifesaving Hunch: How Rosenberg's Unexpected Discovery of Cisplatin Changed Medicine | From Atoms To Words | Arturo Robertazzi

Computational Analysis of Cisplatin-DNA Structures. In my research, I applied QM/MM methods to explore hydrogen bonding and π-stacking in various cisplatin-DNA models, including a platinated double-stranded DNA fragment. While consistent with previous experimental and DFT findings, my study provided further atomistic-level insight into the mechanism of DNA disruption by cisplatin, highlighting the secondary role of π-stacking loss. This reduction contributes to the pronounced distortion in the DNA structure (up to 20-40°), a critical factor in cisplatin’s overarching anticancer effect. I took great pride in the preliminary work for this study, especially fine-tuning a DFT-based approach to predict and estimate π-stacking interactions between aromatic molecules. It was a big deal at that time.
The animation shows the experimental structure of a cisplatin-DNA adduct – Via Protein Data Bank

A final personal touch

You know, the whole cisplatin saga really gets to me. It echoes those groundbreaking moments in science, much like the discovery of graphene, when an unexpected lab result morphs into something truly monumental.

Born from a curious hunch, an experimental anomaly, and a scientist’s ingenuity, cisplatin isn’t just any small molecule; it’s the pioneering force in chemotherapy, offering a lifeline to millions amid their toughest battles.

And the elegance of its mechanism of action—wow!—cisplatin plays a biological beauty and the beast role. It navigates the bloodstream, reaches the cell, undergoes activation, and strategically initiates its cytotoxic impact, targeting the DNA. This process, though straightforward in its essence, unfolds with astonishing biological complexity.

Perhaps my judgment is tinted with bias, given the years I’ve dedicated to it, but I find myself drawn to the story of Rosenberg’s cisplatin in every scientific discussion. It’s a testament to human ingenuity, a highlight of the innate capability within us all. It serves as a reminder that we possess the inventiveness and tenacity necessary to turn a hunch into a breakthrough.

If only we learned to consistently apply this ability to good use, oh man — that would indeed be a world-changing development.

If you enjoyed this dive into the discovery of cisplatin, I’d love to hear your thoughts. Agree, disagree, or have a totally wild theory of your own? Let’s connect! Subscribe to my LinkedIn newsletter and let’s keep the conversation rolling.

Scientific Reading List:

▸ Cisplatin: The First Metal-Based Anticancer Drug – Ghosh 2019
▸ Hydrogen Bonding, Solvation, and Hydrolysis of Cisplatin- Robertazzi 2004
▸ Hydrogen Bonding and Covalent Effects in Binding of Cisplatin to Purine Bases – Robertazzi 2005
▸ A QM/MM Study of Cisplatin–DNA Oligonucleotides – Robertazzi 2006

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