Jadomycins: A potential chemotherapy for multi-drug resistant metastatic breast cancer
Esther P Bonitto1, Brendan T McKeown1,2, Kerry B Goralski1,2,3,4
1Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
Breast cancer causes the most cancer fatalities in women worldwide. Approximately one-third of breast cancers metastasize, or spread from primary tumors to other tissues, and have a 70% 5-year mortality rate. Current breast cancer treatments like doxorubicin and paclitaxel become ineffective when breast cancer cells develop multi-drug resistance and overexpress ATP-binding cassette transporters, as the transporters cause a substantial efflux of the chemotherapies. Jadomycins, a group of molecules isolated from Streptomyces venezuelae ISP5230, are shown to be cytotoxic against a variety of cancers, especially breast cancer. Furthermore, jadomycins retain their cytotoxic properties in multi-drug resistant breast cancer cells, as they are not expelled through ATP-binding cassette transporters. Here, we describe the research that supports the potential use of jadomycins as a novel chemotherapy in the treatment of multi-drug resistant, metastatic breast cancer. We present the supportive findings, as well as the mechanisms of action investigated thus far. These include copper-mediated reactive oxygen species generation, aurora B kinase inhibition, and topoisomerase IIα and IIβ inhibition. We also suggest future directions of jadomycin research, which will help to determine if jadomycins can be used as a breast cancer chemotherapy in clinical practice.
Insights
Jadomycins show promise as a new breast cancer chemotherapy. These compounds are effective against multi-drug resistant and metastatic breast cancer cells, unlike traditional treatments.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Breast cancer is a leading cause of cancer death in women globally.
- Metastatic breast cancer has a high mortality rate, and resistance to chemotherapy is a significant challenge.
- Multidrug resistance in breast cancer is often mediated by ATP-binding cassette transporters, which efflux chemotherapeutics.
Purpose of the Study:
- To investigate the potential of jadomycins as a novel chemotherapy for multidrug-resistant (MDR) metastatic breast cancer.
- To evaluate the efficacy and mechanisms of action of jadomycins in preclinical models.
Main Methods:
- Isolation of jadomycins from Streptomyces venezuelae ISP5230.
- Assessment of jadomycin cytotoxicity against various cancer cell lines, including MDR breast cancer cells.
- Investigation of mechanisms including reactive oxygen species generation, aurora B kinase inhibition, and topoisomerase II inhibition.
Main Results:
- Jadomycins exhibit potent cytotoxicity against breast cancer cells.
- Jadomycins are effective against MDR breast cancer cells, bypassing efflux mechanisms.
- Identified mechanisms of action include ROS generation and inhibition of key enzymes like aurora B kinase and topoisomerase II.
Conclusions:
- Jadomycins represent a promising new therapeutic strategy for treating MDR metastatic breast cancer.
- Further research is warranted to establish jadomycins' clinical utility in breast cancer treatment.
More Related Videos
19:44Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
Published on: May 30, 2012
06:02Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers
Published on: February 20, 2017
Related Concept Videos
02:56Treatment Resistant Cancers
01:28Antimicrobial Effectiveness
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:29Chemotherapy-Induced Nausea and Vomiting: Dopamine Receptor Antagonists
Phenothiazines, such as prochlorperazine...
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...