Anticancer drug candidate inhibits lethal aggregation of mutant tumor suppressor protein

January 14, 2019

Cancer is a multidisciplinary disease, with different mutations leading to different prognoses and treatment necessities. Among the most important mutation targets in cancers, affecting more than 50% of all cancer cases, is TP53. This gene gives rise to a protein that is a key regulator in the cell, called p53. When mutated, this protein forms amyloid structures that accumulate in the cell, causing cancers that tend to have a worse prognosis. A group of Brazilian researchers has shown that a synthetic compound, PRIMA-1, reverses mutant p53 aggregate accumulation. The novel study is the first to demonstrate the action of PRIMA-1 on the inhibition of aggregates of the mutant p53 protein. The results are published in the Journal of Biological Chemistry.

Mutations in the TP53 gene will kill hundreds of million people alive today if new therapies are not developed. Mutant p53 not only undergoes misfolding but also aggregation, similar to that observed with amyloids, playing a crucial role in the development of cancer through loss of function, negative dominance and gain of function. In earlier studies, researchers led by Jerson Silva at the Federal University of Rio de Janeiro (UFRJ) have pointed out that mutant p53 aggregation is an excellent target for development of therapeutic drugs against cancer.

Now, the same group shows that PRIMA-1 (p53 reactivation with induction of massive apoptosis-1) and its primary active metabolite, 2-methylene-3-quinuclidinone (MQ), can restore aggregated mutant p53 to a native form. PRIMA-1 and MQ had been previously shown to convert unfolded p53 mutants to a native conformation that induces apoptosis and activates several p53 target genes. This study provides the first demonstration that PRIMA-1 can rescue amyloid-state p53 mutants, a strategy that could be further explored as a cancer treatment. Its derivative PRIMA-1MET is now in Phase II clinical trials and the Brazilian results may contribute to the development of a new anticancer drug. The research was conducted in vitro and in tumor cell lines of breast cancer and ovarian carcinoma.

"The findings are crucial in establishing the mutant p53 aggregation as a highly promising target for cancer therapy and we are working hard on this subject", states Luciana P. Rangel, first author of the study, from the Faculty of Pharmacy of UFRJ and a member of the National Institute of Science and Technology of Structural Biology and Bioimaging (INBEB).
The paper entitled "p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells" is available online in the Journal of Biological Chemistry website, at

Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem (INBEB)

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to