Table 2
| Agent | Agent Class | Mechanism of Drug Action | Possible mechanism of Resistance in p53 ... | Reference |
| Cisplatin | Platinum-based complex | Inhibition of DNA replication by DNA cro ... | Mutant p53 upregulates Nrf2 (nuclear fac ... | [ 46 – 50] |
| Temozolomide | Alkylating agent | DNA damage and inhibition of cell divisi ... | In temozolomide-resistant glioma cells, ... | [ 15, 51 – 56] |
| Doxorubicin | Anthracycline | Intercalation into DNA and inhibition of ... | TP53 mutations affecting or disrupting t ... | [ 57 – 62] |
| Gemcitabine | Antimetabolite | Interference of normal metabolism due to ... | Gemcitabine treatment stabilizes mutant ... | [ 63 – 65] |
Can mutant p53 cause chemo-resistance of tumor?
In conclusion, our findings demonstrate mutant p53 may cause chemo-resistance of tumor because of inactivating PUMA transcription, which prompts some new insights for clinical therapy of cancer patients with mutant p53.
Is it possible to restore p53's function to treat cancer?
Due to the high frequency of p53 mutations in human tumors, this tumor suppressor is an important target for novel anticancer therapies. Several research teams have dealt with the possibilities of restoring p53's function to treat cancer and their efforts showed worthwhile outcomes.
How does p53 polymorphism affect cellular sensitivity to anticancer drugs?
Furthermore polymorphism in codon 72 (Arg/Pro) of p53 affects cellular sensitivity to anticancer drugs such as doxorubicin through inhibition of p73, a protein related to p53. [57–62] Gemcitabine Antimetabolite
How do you fix p53 mutations?
Reactivating p53 with Drugs. Another experimental cancer therapy in development involves “patching” mutated p53 genes in cells so they can function normally again. Doctors could potentially use this medicine to treat cancer and prevent it by repairing defective p53 genes before cells have the chance to become cancerous.
Why will the p53 gene no longer function properly?
Most of the TP53 gene mutations involved in HNSCC change single amino acids in p53; these changes impair the protein's function. Without functioning p53, cell proliferation is not regulated. As a result, cells accumulate DNA damage and continue to divide in an uncontrolled way, leading to tumor growth.
What happens if p53 is mutated?
Mutations (changes) in the p53 gene may cause cancer cells to grow and spread in the body. These changes have been found in a genetic condition called Li-Fraumeni syndrome and in many types of cancer.
Why did p53 gene therapy fail in ovarian cancer?
Indeed, p53's ability to induce apoptosis in aberrant cells was exploited in clinical trials in the late 1990s, but the therapy failed due to the DN effect, inability to overcome other mutated oncogenes, immunogenic issues with adenoviral delivery, and inefficient targeting of cancer cells [9].
Are there any current treatments for p53 mutations?
Another experimental cancer therapy in development involves “patching” mutated p53 genes in cells so they can function normally again. Doctors could potentially use this medicine to treat cancer and prevent it by repairing defective p53 genes before cells have the chance to become cancerous.
Why is the p53 mutation so common?
This suggests that an enhanced mutation rate plus selection for conservation of a key amino acid drives hotspot mutations in the TP53 gene. It remains possible that several differences in the gain-of-function phenotypes of TP53 alleles are selected for by cancers, giving rise to hotspot mutations.
Is p53 mutated in all cancers?
Therefore, p53 is considered the “Guardian of the genome” to prevent accumulation of oncogenic mutations that lead to malignant tumor (1, 2). Mutations in TP53 are found in over half of human cancers, thus is known as the most commonly mutated gene in human cancers (3, 4).
Is p53 an oncogene or a Tumour suppressor?
The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood.
Is p53 mutation dominant or recessive?
p53 mutants are recessive for transactivation of p21WAF1/CIP1 but dominant negative for transactivation of Bax. p53 mutants previously found in human cancers were analyzed for the ability to perform wild-type p53-associated functions.
What is p53 inhibitor?
Santa Cruz Biotechnology now offers a broad range of p53 Inhibitors. p53 is a DNA-binding tumor suppressor, which upregulates growth arrest and apoptosis-related genes in response to stress signals, thereby influencing programmed cell death, cell differentiation and cell cycle control mechanisms.
What is the most commonly altered gene in cancer?
TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers ...
Is TP53 a target for cancer?
Mutant p53 as a target for cancer treatment. TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, s ….
What is the target of TP53?
Targeting p53 for the treatment of cancer. Dysfunction of the TP53 (p53) gene occurs in most if not all human malignancies. Two principal mechanisms are responsible for this dysfunction; mutation and downregulation of wild-type p53 mediated by MDM2/MDM4.
Why is TP53 a highly attractive T?
Because of its almost universal inactivation in malignancy, p53 is a highly attractive t …. Dysfunction of the TP53 (p53) gene occurs in most if not all human malignancies. Two principal mechanisms are responsible for this dysfunction; mutation and downregulation of wild-type p53 mediated by MDM2/MDM4.
What happens when the p53 gene is corrupted?
When the p53 gene itself is corrupted, however, cells lose a natural safeguard against becoming cancerous. Doctors have observed that more than half of human cancer cases involve mutated p53 genes.
What is the treatment for mesothelioma?
Gene therapy is one of several new treatments that researchers are hoping will bring us closer to a cure for mesothelioma. Another form of gene therapy in development for mesothelioma includes suicide gene therapy.
What is the most important gene in the human genome?
In human DNA, certain genes are responsible for preventing cells from becoming cancerous. The p53 gene is one of the most important of these tumor-suppressor genes. Healthy cells can become cancerous when carcinogens, such as asbestos, damage their DNA and cause them to start dividing and reproducing uncontrollably.
Can mutated p53 genes be replaced?
If doctors find an effective way to repair or replace mutated p53 genes in cancer cells, it could lead to a radical improvement in the treatment of many types of cancer, including mesothelioma and other asbestos-related cancers. Many researchers believe the emerging science of gene therapy holds the key.
Is gene therapy a reliable way to deliver the tumor suppressor gene to the cells that need it?
The great challenge of gene therapy is to find a reliable way to deliver the tumor-suppressor gene to the cells that need it. Researchers have tested a few different DNA-delivery vehicles, or vectors, on several types of cancer, but so far, none of these gene-therapy techniques has been approved by the FDA for mesothelioma treatment.
Can restoring p53 be combined with radiation?
A gene therapy treatment based on restoring p53 could be safely combined with traditional cancer treatments such as surgery, chemotherapy or radiation therapy to increase the overall effectiveness of the treatment plan. Gene therapy is one of several new treatments that researchers are hoping will bring us closer to a cure for mesothelioma.
Can a virus deliver p53?
Many researchers have tried using genetically engineered viruses to deliver p53 genes to cancer cells. Researchers first remove the dangerous viral DNA from the viruses to ensure they cannot cause an infection in the patient. Then the researchers inject the altered viruses directly into the tumors.
Abstract
Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression.
Main Text
p53 is one of the most intensively studied tumor suppressor proteins, with mutations that lead to loss of wild-type p53 activity frequently detected in many different tumor types.
Acknowledgments
We thank Cancer Research UK, AICR, and the Royal Society/Wellcome trust for funding support.
Footnotes
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
What is the role of p53 in cancer?
Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy. Tumor suppressor p53 plays a central role in tumor suppression. p53 is the most frequently mutated gene in human cancer, and over half of human cancers contain p53 mutations.
Is Mutp53 a cancer drug?
Recently, mutp53 has become an attractive target for cancer therapy. Further understanding of the mechanisms underlying mutp53 protein accumulation and gain-of-function will accelerate the development of targeted therapies for human cancer harboring mutp53.
What is the role of mutant p53 in cancer?
In addition to playing roles in the genesis and progression of cancer, mutant p53 also appears to play a significant role in the response to cancer therapy .
Is mutant p53 a prognostic factor?
However, it still remains unclear whether the presence of mutant p53 in tumors can serve as a reliable prognostic factor and aid in treatment planning. Thus, as genomic analysis of patient tumors becomes more cost effective, the role of mutant p53 in tumor responses from cancer therapy ultimately needs to be addressed.
Does P53 affect cancer?
In addition to playing roles in the genesis and progression of cancer, mutant p53 also appears to play a significant role in the response to cancer therapy. In response to chemotherapy and radiation, two mainstays of cancer treatment, most cancer cells harboring p53 mutations show a reduced sensitiv ….