Cytochalasans are known as inhibitors of actin polymerization and for their cytotoxic and migrastatic activity. In this study, we synthesized a series of cytochalasin derivatives that lack a macrocyclic moiety, a structural element traditionally considered essential for their biological activity. We focused on substituting the macrocycle with simple aryl-containing sidechains, and we have also synthesized compounds with different substitution patterns on the cytochalasin core. The cytochalasin analogues were screened for their migrastatic and cytotoxic activity. Compound 24 which shares the substitution pattern with natural cytochalasins B and D exhibited not only significant in vitro migrastatic activity towards BLM cells but also demonstrated inhibition of actin polymerization, with no cytotoxic effect observed at 50 μM concentration. Our results demonstrate that even compounds lacking the macrocyclic moiety can exhibit biological activities, albeit less pronounced than those of natural cytochalasins. However, our findings emphasize the pivotal role of substituting the core structure in switching between migrastatic activity and cytotoxicity. These findings hold significant promise for further development of easily accessible cytochalasan analogues as novel migrastatic agents.
- Publication type
- Journal Article MeSH
Traditionally, anticancer therapies focus on restraining uncontrolled proliferation. However, these cytotoxic therapies expose cancer cells to direct killing, instigating the process of natural selection favoring survival of resistant cells that become the foundation for tumor progression and therapy failure. Recognizing this phenomenon has prompted the development of alternative therapeutic strategies. Here we propose strategies targeting cancer hallmarks beyond proliferation, aiming at re-educating cancer cells towards a less malignant phenotype. These strategies include controlling cell dormancy, transdifferentiation therapy, normalizing the cancer microenvironment, and using migrastatic therapy. Adaptive resistance to these educative strategies does not confer a direct proliferative advantage to resistant cells, as non-resistant cells are not subject to eradication, thereby delaying or preventing the development of therapy-resistant tumors.
- MeSH
- Drug Resistance, Neoplasm MeSH
- Humans MeSH
- Tumor Microenvironment * MeSH
- Neoplasms * therapy MeSH
- Cell Proliferation MeSH
- Antineoplastic Agents therapeutic use pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Solid tumor metastases cause most cancer-related deaths. The prevention of their occurrence misses suitable anti-metastases medicines newly labeled as migrastatics. The first indication of migrastatics potential is based on an inhibition of in vitro enhanced migration of tumor cell lines. Therefore, we decided to develop a rapid test for qualifying the expected migrastatic potential of some drugs for repurposing. The chosen Q-PHASE holographic microscope provides reliable multifield time-lapse recording and simultaneous analysis of the cell morphology, migration, and growth. The results of the pilot assessment of the migrastatic potential exerted by the chosen medicines on selected cell lines are presented.
- Publication type
- Journal Article MeSH
Most cancer-related deaths among patients with solid tumors are caused by metastases. Migrastatic strategies represent a unique therapeutic approach to prevent all forms of cancer cell migration and invasion. Because the migration machinery has been shown to promote metastatic dissemination, successful migrastatic therapy may reduce the need for high-dose cytotoxic therapies that are currently used to prevent the risk of metastatic dissemination. In this review we focus on anti-invasive and antimetastatic strategies that hold promise for the treatment of solid tumors. The best targets for migrastatic therapy would be those that are required by all forms of motility, such as ATP availability, mitochondrial metabolism, and cytoskeletal dynamics and cell contractility.
- MeSH
- Humans MeSH
- Neoplasms * drug therapy MeSH
- Cell Movement MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Metastasis accounts for the highest mortality rates in solid tumor cancer patients. However, research and development have neglected this most lethal characteristic and, instead, have concentrated on the hallmarks of cancer that make tumor cells highly proliferative and distinctive from nonmalignant cells. The concentration on invasion and metastasis can be one of the most meaningful advancements in cancer investigation. Importantly, metastasis-free survival (MFS) was recently approved by the Food and Drug Administration (FDA) as a novel primary endpoint in clinical trials and has been used to evaluate the prognosis of patients with nonmetastatic castration-resistant prostate cancer and soft tissue sarcoma. This new definition enables to shift the focus of research and development in cancer therapeutics toward metastasis and to change the emphasis from using tumor shrinkage as a benchmark for indicating the efficacy of treatment to using MFS as a more representative endpoint for antimetastatic drugs. This perspective outlines the possibility to use this novel endpoint in other solid cancers, and examples of large clinical trials are given in which MFS is defined as an endpoint and/or in which antimetastatic strategies are being examined. These advances now open the door for the rapid development of antimetastatic therapies, which could be used in combination with standard cytotoxic cancer therapies. With pioneer research on metastasis prevention on the rise and the underlying biomechanisms of tumor cell motility and invasion explored further than ever before, we believe an intensified focus on antimetastatic properties will shape this era of cancer translational research.
- MeSH
- Progression-Free Survival MeSH
- Neoplasm Invasiveness MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Neoplasms drug therapy metabolism mortality pathology MeSH
- Cell Movement drug effects MeSH
- Antineoplastic Agents therapeutic use MeSH
- Endpoint Determination MeSH
- Translational Research, Biomedical MeSH
- Research Design MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The molecular weight (Mw) of dextran derivatives, such as regioselectively oxidized dicarboxydextran (DXA), is greatly influencing their faith in an organism, which could be possibly used to improve anticancer drug delivery. Here we present a modified method of sulfonation-induced chain scission allowing direct and accurate control over the Mw of DXA without increasing its polydispersity. Prepared DXA derivatives (Mw = 10-185 kDa) have been conjugated to cisplatin and the Mw of the carrier found to have a significant impact on cisplatin release rates, in vitro cytotoxicity, and migrastatic potential. Conjugates with the high-Mw DXA showed particularly increased anticancer efficacy. The best conjugate was four times more effective against malignant prostatic cell lines than free cisplatin and significantly inhibited the ovarian cancer cell migration. This was traced to the characteristics of spontaneously formed cisplatin-crosslinked DXA nanogels influenced by Mw of DXA and amount of loaded cisplatin.
- MeSH
- Adenocarcinoma drug therapy metabolism MeSH
- A549 Cells MeSH
- Cisplatin chemistry pharmacology MeSH
- Dextrans chemistry MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Molecular Weight MeSH
- Prostatic Neoplasms drug therapy metabolism MeSH
- Ovarian Neoplasms drug therapy metabolism MeSH
- Neoplasms drug therapy metabolism MeSH
- Nanogels chemistry MeSH
- Drug Carriers chemistry MeSH
- Oxidation-Reduction MeSH
- Cell Movement drug effects MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. SIGNIFICANCE: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2289/F1.large.jpg.
- MeSH
- Cell Death drug effects MeSH
- PC-3 Cells MeSH
- Iron Chelating Agents administration & dosage MeSH
- Deferoxamine administration & dosage MeSH
- Heme metabolism MeSH
- Carcinogenesis drug effects MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Mitochondria drug effects metabolism MeSH
- Mitophagy drug effects MeSH
- Mice, Inbred BALB C MeSH
- Mice MeSH
- Neoplasms drug therapy metabolism pathology MeSH
- Cell Movement drug effects MeSH
- Cell Proliferation drug effects MeSH
- Reactive Oxygen Species metabolism MeSH
- Signal Transduction drug effects MeSH
- Tumor Burden drug effects MeSH
- Xenograft Model Antitumor Assays MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The concept of 'migrastatics' allows the development of a new drug class that is neither cytotoxic nor antiproliferative but is solely directed towards inhibition of cancer cell motility. Given that the regulatory pathway is open, and migrastatic candidates have been described, it is the right time to enter a new era of antimetastatic treatment.
- MeSH
- Neoplasm Invasiveness genetics MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Cell Line, Tumor MeSH
- Neoplasms complications MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term 'migrastatics' for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.
- MeSH
- Drug Resistance, Neoplasm MeSH
- Molecular Targeted Therapy MeSH
- Humans MeSH
- Neoplasm Metastasis drug therapy MeSH
- Biomarkers, Tumor MeSH
- Neoplasms drug therapy etiology metabolism pathology MeSH
- Drug Discovery * MeSH
- Cell Movement drug effects MeSH
- Antineoplastic Agents chemistry pharmacology therapeutic use MeSH
- Signal Transduction drug effects MeSH
- Drug Synergism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
