Cisplatin, a platinum-based coordination compound, is a foundational chemotherapy drug. Its discovery revolutionized the treatment of several cancers, including testicular, ovarian, and bladder malignancies, leading to increased survival rates. The drug works by acting as a DNA-damaging agent, preventing the uncontrolled division that defines cancer cells. Approved by the FDA in 1978, it remains a foundational component of many modern cancer treatment regimens.
Drug Entry and Intracellular Activation
For Cisplatin to initiate its cytotoxic effects, it must successfully navigate the cell membrane and become chemically active inside the cancer cell. The drug, which is electrically neutral in the bloodstream, enters the cell primarily through passive diffusion or active transport mechanisms. The human copper transporter 1 (CTR1) is a major pathway for Cisplatin uptake, utilizing the cell’s natural system for internalizing metal ions.
Once the drug is inside the cytoplasm, it undergoes a chemical transformation known as aquation or hydrolysis. In the high-chloride environment of the blood plasma (around 100 mM), the two chloride atoms on the Cisplatin molecule keep the drug inert. However, the intracellular concentration of chloride is much lower (3 to 20 mM). This low concentration allows water molecules to displace the chloride atoms, transforming the neutral Cisplatin into a positively charged, highly reactive platinum species. This activated complex is an electrophile, ready to seek out and bind to electron-rich molecules, with DNA being its ultimate target.
Primary Target: DNA Binding and Cross-Links
The activated platinum species rapidly moves toward the nucleus, where it targets the DNA. The platinum ion preferentially forms strong covalent bonds with the nitrogen atoms, specifically the N7 position, on the purine bases of DNA. Cisplatin shows a particular affinity for Guanosine bases, which is the site of the most frequent damage.
The binding of the platinum atom to the DNA bases results in the formation of lesions called platinum-DNA adducts, which are the main source of the drug’s cytotoxic power. The majority of these lesions are intrastrand cross-links. These links form between two adjacent bases on the same DNA strand, most commonly between two Guanosines (d(GpG)) or a Guanosine and an Adenosine (d(ApG)).
The formation of these intrastrand cross-links physically distorts the DNA helix, causing a significant bend or “kink” in the structure. This distortion is recognized by DNA-binding proteins, such as high-mobility group (HMG) proteins, which bind to the bent DNA. By shielding the lesion, these proteins prevent the enzymes responsible for DNA replication and transcription from accessing the template. A smaller, but more lethal, type of damage involves interstrand cross-links, where the platinum atom bridges bases on opposite DNA strands. These lesions are extremely difficult for the cell to repair, leading to a complete block of DNA strand separation and replication.
The Fatal Cellular Consequences
The DNA damage caused by Cisplatin adducts triggers a cascade of events that ultimately leads to the cancer cell’s demise. The primary response of the cell to this extensive DNA damage is to activate checkpoints that halt the cell cycle. This arrest typically occurs in the S phase, where DNA is replicated, or the G2 phase, which precedes cell division, preventing the damaged DNA from being passed on to daughter cells.
The purpose of this cell cycle arrest is to provide time for DNA repair mechanisms to excise the platinum adducts and restore the DNA structure. If the repair machinery is successful, the cell can survive; however, if the damage is too widespread or the repair is insufficient, the cell is forced into programmed cell death.
This final, irreversible step is known as apoptosis, a highly regulated self-destruction process. Signaling pathways are activated, often involving the tumor suppressor protein p53, which senses the persistent DNA damage. When p53 is functional, it initiates the transcription of genes that commit the cell to apoptosis, ensuring the cell dies in a controlled manner.
Clinical Application and Resistance Mechanisms
Cisplatin’s clinical track record, particularly in treating testicular cancer, has cemented its place in oncology. Despite its effectiveness, the development of drug resistance is a challenge, which can be inherent to the tumor or acquired during treatment. Cancer cells deploy several mechanisms to evade the drug’s action, limiting its therapeutic window.
Resistance Mechanisms
One primary strategy involves reducing the amount of active drug that reaches the DNA target. Cells may decrease the expression of influx transporters like CTR1, or increase the activity of efflux pumps that push the drug back out.
Another method is detoxification, where the drug is chemically inactivated inside the cell. This involves high levels of sulfhydryl-containing molecules, such as glutathione, which bind to the activated platinum species, sequestering it before it reaches the DNA.
A third resistance mechanism is the enhancement of DNA repair. Cells upregulate their nucleotide excision repair (NER) pathways, which remove the bulky platinum-DNA adducts. By quickly excising the damage, the cancer cell prevents the persistent DNA lesions that trigger cell cycle arrest and apoptosis, allowing the cell to continue dividing.