76
H. Zhu et al.
oncogene-induced inhibition of gap junction-mediated cellular communication in
ras-transformed epithelial and human lung carcinoma cells [213]. Chaetoglobosin
K (273) also induced apoptosis and G2 cell cycle arrest through the p53-dependent
pathway in cisplatin-resistant ovarian cancer cells [214], and it inhibited effectively
tumor angiogenesis through downregulation of VEGF-binding HIF-1a in vivo [215].
Asperchalasine A (455) induced significant G1-phase cell cycle arrest by selectively
inhibiting cyclin A, CDK2, and CDK6 in cancerous, but not normal cells, highlighting
it as a potentially selective cell cycle regulator against cancer cells [193]. Epicochalasines A and B (461 and 462) both induced significant G2/M-phase cell cycle arrest
and induced apoptosis in leukemia cells through the activation of caspase-3 and the
degradation of PARP [196].
Moreover, the unique microfilament-directed mechanisms of cytochalasans have
made them of interest for drug synergy investigations with existing drug therapy
for treating cancer. Early studies have shown drug synergy between cytochalasin
B (110) and cytarabine as well as vincristine. These have provided compelling
evidence that cytochalasin B (110) and its reduced congener may have clinically
applicable synergistic potential [216]. More specifically, concomitant administration of cytochalasin B (110) and vincristine substantially reduced the clonogenicity
potential of U937 human monocytic leukemia cells, thereby potently inhibiting
their propensity to proliferate [217]. Both cytochalasin B (110) and its congener
21,22-dihydrocytochalasin B (DiHCB) demonstrated considerable drug synergy with
doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells in vitro. In turn,
cytochalasins B (110) and D (2) substantially increased the life expectancy of mice
challenged with P388/S and P388/ADR leukemia xenografts in vivo [218]. Further,
due to cytokinesis inhibition potentiated by the cytochalasans, normal or multidrugresistant neoplastic cells become enlarged and multinucleated, which makes them
suitable targets for microtubule-directed (paclitaxel), nucleic acid-directed (doxorubicin) agents, or other physicochemical treatment modalities, such as experimental
sonodynamic therapy (SDT), an ultrasound therapy that preferentially damages cells
based on their size. For example, pulsed low-frequency ultrasound in the 20–40 kHz
range is able to induce preferential destruction of neoplastic cells enlarged by treatment with cytoskeletal-directed agents [217, 219]. The most well-known mechanism
of action is the concomitant perturbation of the cell cycle via microtubule-targeting
G2/M arrest and microfilament-targeting cytokinesis inhibition. For multidrugresistant neoplastic cells, Trendowski et al., using the multidrug-resistant SKVLB1
cell line as a model, demonstrated that cytochalasans appear to inhibit the activity
of P-glycoprotein (P-gp) and potentially other ABC transporters, and may have a
novel type of activity against multidrug-resistant neoplastic cells that overexpress
drug efflux proteins [220].
In conclusion, the actin cytoskeleton is vital for carcinogenesis and subsequent pathology, and microfilament-targeting cytochalasans have raised considerable interest as cancer-related drug candidates [160, 221]. When used as a single
agent, the narrow therapeutic index of cytochalasin derivatives prevents their clinical
use, and to date no microfilament-directed agent has entered a clinical trial [222].
H. Zhu et al.
oncogene-induced inhibition of gap junction-mediated cellular communication in
ras-transformed epithelial and human lung carcinoma cells [213]. Chaetoglobosin
K (273) also induced apoptosis and G2 cell cycle arrest through the p53-dependent
pathway in cisplatin-resistant ovarian cancer cells [214], and it inhibited effectively
tumor angiogenesis through downregulation of VEGF-binding HIF-1a in vivo [215].
Asperchalasine A (455) induced significant G1-phase cell cycle arrest by selectively
inhibiting cyclin A, CDK2, and CDK6 in cancerous, but not normal cells, highlighting
it as a potentially selective cell cycle regulator against cancer cells [193]. Epicochalasines A and B (461 and 462) both induced significant G2/M-phase cell cycle arrest
and induced apoptosis in leukemia cells through the activation of caspase-3 and the
degradation of PARP [196].
Moreover, the unique microfilament-directed mechanisms of cytochalasans have
made them of interest for drug synergy investigations with existing drug therapy
for treating cancer. Early studies have shown drug synergy between cytochalasin
B (110) and cytarabine as well as vincristine. These have provided compelling
evidence that cytochalasin B (110) and its reduced congener may have clinically
applicable synergistic potential [216]. More specifically, concomitant administration of cytochalasin B (110) and vincristine substantially reduced the clonogenicity
potential of U937 human monocytic leukemia cells, thereby potently inhibiting
their propensity to proliferate [217]. Both cytochalasin B (110) and its congener
21,22-dihydrocytochalasin B (DiHCB) demonstrated considerable drug synergy with
doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells in vitro. In turn,
cytochalasins B (110) and D (2) substantially increased the life expectancy of mice
challenged with P388/S and P388/ADR leukemia xenografts in vivo [218]. Further,
due to cytokinesis inhibition potentiated by the cytochalasans, normal or multidrugresistant neoplastic cells become enlarged and multinucleated, which makes them
suitable targets for microtubule-directed (paclitaxel), nucleic acid-directed (doxorubicin) agents, or other physicochemical treatment modalities, such as experimental
sonodynamic therapy (SDT), an ultrasound therapy that preferentially damages cells
based on their size. For example, pulsed low-frequency ultrasound in the 20–40 kHz
range is able to induce preferential destruction of neoplastic cells enlarged by treatment with cytoskeletal-directed agents [217, 219]. The most well-known mechanism
of action is the concomitant perturbation of the cell cycle via microtubule-targeting
G2/M arrest and microfilament-targeting cytokinesis inhibition. For multidrugresistant neoplastic cells, Trendowski et al., using the multidrug-resistant SKVLB1
cell line as a model, demonstrated that cytochalasans appear to inhibit the activity
of P-glycoprotein (P-gp) and potentially other ABC transporters, and may have a
novel type of activity against multidrug-resistant neoplastic cells that overexpress
drug efflux proteins [220].
In conclusion, the actin cytoskeleton is vital for carcinogenesis and subsequent pathology, and microfilament-targeting cytochalasans have raised considerable interest as cancer-related drug candidates [160, 221]. When used as a single
agent, the narrow therapeutic index of cytochalasin derivatives prevents their clinical
use, and to date no microfilament-directed agent has entered a clinical trial [222].