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Chemotherapy with cytochalasin congeners in vitro and in vivo against murine models.

Trendowski M, Mitchell JM, Corsette CM, Acquafondata C, Fondy TP - Invest New Drugs (2015)

Bottom Line: Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells.We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro.Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA, mrtrendo@syr.edu.

ABSTRACT
Background Despite inherent differences between the cytoskeletal networks of malignant and normal cells, and the clinical antineoplastic activity of microtubule-directed agents, there has yet to be a microfilament-directed agent approved for clinical use. One of the most studied microfilament-directed agents has been cytochalasin B, a mycogenic toxin known to disrupt the formation of actin polymers. Therefore, this study sought to expand on our previous work with the microfilament-directed agent, along with other less studied cytochalasin congeners. Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells. We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro. For in vivo characterization, cytochalasins B and D were administered intraperitoneally (i.p.) to Balb/c mice challenged with drug sensitive P388-S or multidrug resistant P388/ADR leukemias. Results Cytochalasin B demonstrated higher cytotoxicity against adherent lung carcinoma and melanoma cells than against suspension P388/ADR leukemia cells, as assessed by comparative effects on cell growth, and IC₅₀ and IC₈₀ values. Isobolographic analysis indicated that both cytochalasin B and DiHCB demonstrate considerable drug synergy with ADR against ADR-resistant P388/ADR leukemia, while cytochalasin D exhibits only additivity with ADR against the same cell line. In vivo, cytochalasins B and D substantially increased the life expectancy of mice challenged with P388/S and P388/ADR leukemias, and in some cases, produced long-term survival. Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.

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IC50 Isobolograms of cytochalasins and doxorubicin to determine extent of drug synergy against P388/ADR leukemia. a CB and ADR. b DiHCB and ADR. c CD and ADR
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Fig2: IC50 Isobolograms of cytochalasins and doxorubicin to determine extent of drug synergy against P388/ADR leukemia. a CB and ADR. b DiHCB and ADR. c CD and ADR

Mentions: Despite the lower activity of cytochalasin B in P388/ADR leukemia, it still produced a substantial synergistic effect with ADR against the ADR-resistant cell line, as assessed by the IC50 (Fig. 2a) and IC80 (Fig. 3a) isobolograms. While low concentrations of cytochalasin B demonstrated marked synergy in the IC80 isobologram, it took a 150 μM concentration for cytochalasin B by itself to reach the IC80 inhibition point. (Fig. 3a). This pattern was also seen in the IC99 cloning isobologram for cytochalasin B/ADR (Fig. 4) where 1.1 mM cytochalasin B is required to reach the IC99 value with the single agent treatment. DiHCB also demonstrated considerable drug synergy with ADR against P388/ADR leukemia, with a smooth curve well under the additivity line being observed in both the IC50 and IC80 isobolograms (Figs. 2b and 3b). Cytochalasin D demonstrated little to no synergy with ADR against P388/ADR leukemia (Figs. 2c and 3c). Nevertheless, cytochalasin D appeared to be intermediate between DiHCB and cytochalasin B in regards to inhibiting growth as single agents at their IC50 and IC80 values. DiHCB produced IC50 and IC80 inhibitions at 28 μM and 48 μM respectively. Cytochalasin B required 100 μM and 150 μM to reach IC50 and IC80. Cytochalasin D required 42 μM and 68 μM to reach IC50 and IC80 respectively. (Figs. 2 and 3).Fig. 2


Chemotherapy with cytochalasin congeners in vitro and in vivo against murine models.

Trendowski M, Mitchell JM, Corsette CM, Acquafondata C, Fondy TP - Invest New Drugs (2015)

IC50 Isobolograms of cytochalasins and doxorubicin to determine extent of drug synergy against P388/ADR leukemia. a CB and ADR. b DiHCB and ADR. c CD and ADR
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4387261&req=5

Fig2: IC50 Isobolograms of cytochalasins and doxorubicin to determine extent of drug synergy against P388/ADR leukemia. a CB and ADR. b DiHCB and ADR. c CD and ADR
Mentions: Despite the lower activity of cytochalasin B in P388/ADR leukemia, it still produced a substantial synergistic effect with ADR against the ADR-resistant cell line, as assessed by the IC50 (Fig. 2a) and IC80 (Fig. 3a) isobolograms. While low concentrations of cytochalasin B demonstrated marked synergy in the IC80 isobologram, it took a 150 μM concentration for cytochalasin B by itself to reach the IC80 inhibition point. (Fig. 3a). This pattern was also seen in the IC99 cloning isobologram for cytochalasin B/ADR (Fig. 4) where 1.1 mM cytochalasin B is required to reach the IC99 value with the single agent treatment. DiHCB also demonstrated considerable drug synergy with ADR against P388/ADR leukemia, with a smooth curve well under the additivity line being observed in both the IC50 and IC80 isobolograms (Figs. 2b and 3b). Cytochalasin D demonstrated little to no synergy with ADR against P388/ADR leukemia (Figs. 2c and 3c). Nevertheless, cytochalasin D appeared to be intermediate between DiHCB and cytochalasin B in regards to inhibiting growth as single agents at their IC50 and IC80 values. DiHCB produced IC50 and IC80 inhibitions at 28 μM and 48 μM respectively. Cytochalasin B required 100 μM and 150 μM to reach IC50 and IC80. Cytochalasin D required 42 μM and 68 μM to reach IC50 and IC80 respectively. (Figs. 2 and 3).Fig. 2

Bottom Line: Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells.We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro.Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA, mrtrendo@syr.edu.

ABSTRACT
Background Despite inherent differences between the cytoskeletal networks of malignant and normal cells, and the clinical antineoplastic activity of microtubule-directed agents, there has yet to be a microfilament-directed agent approved for clinical use. One of the most studied microfilament-directed agents has been cytochalasin B, a mycogenic toxin known to disrupt the formation of actin polymers. Therefore, this study sought to expand on our previous work with the microfilament-directed agent, along with other less studied cytochalasin congeners. Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells. We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro. For in vivo characterization, cytochalasins B and D were administered intraperitoneally (i.p.) to Balb/c mice challenged with drug sensitive P388-S or multidrug resistant P388/ADR leukemias. Results Cytochalasin B demonstrated higher cytotoxicity against adherent lung carcinoma and melanoma cells than against suspension P388/ADR leukemia cells, as assessed by comparative effects on cell growth, and IC₅₀ and IC₈₀ values. Isobolographic analysis indicated that both cytochalasin B and DiHCB demonstrate considerable drug synergy with ADR against ADR-resistant P388/ADR leukemia, while cytochalasin D exhibits only additivity with ADR against the same cell line. In vivo, cytochalasins B and D substantially increased the life expectancy of mice challenged with P388/S and P388/ADR leukemias, and in some cases, produced long-term survival. Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.

Show MeSH
Related in: MedlinePlus