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
Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity are known and used, they often fail to achieve satisfactory long-term patient outcomes and survival. Recently, immunotherapy has shown success in patients by harnessing important interactions between the immune system and cancer. However, many of these therapies lead to frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, in severe cases, fatalities. New therapeutic approaches like intratumoral immunotherapy, characterized by reduced side effects, cost, and systemic toxicity, offer promising prospects for future applications in clinical oncology. In the context of locally advanced or metastatic cancer, combining diverse immunotherapeutic and other treatment strategies targeting multiple cancer hallmarks appears crucial. Such combination therapies hold promise for improving patient outcomes and survival and for promoting a sustained systemic response. This review aims to provide a current overview of immunotherapeutic approaches, specifically focusing on the intratumoral administration of drugs in patients with locally advanced and metastatic cancers. It also explores the integration of intratumoral administration with other modalities to maximize therapeutic response. Additionally, the review summarizes recent advances in intratumoral immunotherapy and discusses novel therapeutic approaches, outlining future directions in the field.
- Keywords
- advanced and metastatic cancer, cancer, combination therapy, immunotherapy, intratumoral,
- MeSH
- Immunotherapy * methods MeSH
- Injections, Intralesional MeSH
- Combined Modality Therapy MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Neoplasms * therapy immunology pathology 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
The ability of cells to switch between different invasive modes during metastasis, also known as invasion plasticity, is an important characteristic of tumor cells that makes them able to resist treatment targeted to a particular invasion mode. Due to the rapid changes in cell morphology during the transition between mesenchymal and amoeboid invasion, it is evident that this process requires remodeling of the cytoskeleton. Although the role of the actin cytoskeleton in cell invasion and plasticity is already quite well described, the contribution of microtubules is not yet fully clarified. It is not easy to infer whether destabilization of microtubules leads to higher invasiveness or the opposite since the complex microtubular network acts differently in diverse invasive modes. While mesenchymal migration typically requires microtubules at the leading edge of migrating cells to stabilize protrusions and form adhesive structures, amoeboid invasion is possible even in the absence of long, stable microtubules, albeit there are also cases of amoeboid cells where microtubules contribute to effective migration. Moreover, complex crosstalk of microtubules with other cytoskeletal networks participates in invasion regulation. Altogether, microtubules play an important role in tumor cell plasticity and can be therefore targeted to affect not only cell proliferation but also invasive properties of migrating cells.
- Keywords
- 3D migration, amoeboid, cancer, invasion plasticity, mesenchymal, microtubules,
- Publication type
- Journal Article MeSH
- Review MeSH
