Exploiting the cytoskeletal filaments of neoplastic cells to potentiate a novel therapeutic approach

Abstract

Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate filament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo efficacy, suggesting that cytoskeletal filaments may be exploited to supplement chemotherapeutic approaches currently used in the clinical setting. Therefore, this review is intended to expose academics and clinicians to the tremendous variety of cytoskeletal filament-directed agents that are currently available for further chemotherapeutic evaluation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage malignant cells are discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents.

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

“…This is supported by the G 2 /M cell cycle arrest activity observed after Hsp90 inhibition, as concomitant inhibition of mitosis at this critical checkpoint and at cytokinesis would likely reduce the ability of malignant cells to carry out a successful mitotic event. Several microfilamentdirected agents of particular interest include cytochalasins and closely related chaetoglobosins, latrunculins, and jasplakinolide, each of which has been comprehensively described in prior reviews [1,152,159]. Although the synergism between Hsp90 inhibitors and microfilament-directed agents is purely theoretical at this point, preclinical investigation of this concomitant approach could validate potentially novel therapeutic strategies.…”

“…Although there are no microfilament-directed agents currently approved by the FDA or other pharmaceutical regulating bodies, these compounds have intriguing therapeutic potential. Antineoplastic mechanisms of these agents include the potentiation of multinucleated cancer cells that are exquisitely sensitive to other forms of chemotherapy via inhibition of cytokinesis, reducing metastatic potential by limiting cell motility and adhesion (as well as inhibiting the secretion of glucosaminidases), and binding ATPbinding cassette (ABC) transporters, thereby enhancing the activity of other chemotherapeutic agents [1,152,153]. Due to their unique mechanisms of action, microfilament-directed agents have been shown to sensitize malignant cells to mTOR inhibitors, nucleic acid-directed agents and microtubule-directed agents [154][155][156][157][158].…”

“…Traditionally, agents designed for cancer chemotherapy rely on the principal that malignant cells have higher proliferation rates than normal cells, enabling the selective poisoning of malignant tissue with agents that disrupt vital components of the cell cycle. Specifically, these traditional antineoplastic agents target either nucleic acids and proteins involved in DNA synthesis and transcription, or microtubules responsible for chromosome congression and proper segregation of chromosomes during anaphase [1]. While effective against several hematological malignancies and solid tumors, traditional chemotherapeutic agents are inherently limited by their less than ideal toxicity profiles, producing significant deleterious off target effects in patients that limit dosing schedules.…”

Microtubules and Actin Cytoskeleton of Cryptococcus neoformans as Targets for Anticancer Agents to Potentiate a Novel Approach for New Antifungals

“…Here, several agents used in cancer therapy that inhibit MT or F-actin [4,5,6,7,8] were studied. Their effects on the F-actin cytoskeleton (AC) and the cell division of C. neoformans were investigated by fluorescence and phase-contrast microscopy in the search for new antifungal agents for the inhibition of cell division.…”

Potential Anticancer Properties and Mechanisms of Action of Withanolides

“…Malignant cells have a perturbed cytoskeleton due to the effects of dysplasia and subsequent anaplasia [53]. With so many alterations present in malignant cells, the cytoskeleton provides an ideal opportunity to attain preferential damage.…”