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Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway.

Wang YJ, Li Q, Xiao HB, Li YJ, Yang Q, Kan XX, Chen Y, Liu XN, Weng XG, Chen X, Cai WY, Guo Y, Huang HF, Zhu XX - Drug Des Devel Ther (2015)

Bottom Line: First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26.Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells.In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Capital Medical University, Beijing, People's Republic of China.

ABSTRACT
Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.

No MeSH data available.


Related in: MedlinePlus

CHB exerts anti-MDR activity in vitro.Notes: (A) Chemical structure of CHB; (B) average resistance factors of CHB and four reference agents.Abbreviations: CHB, chamaejasmin B; MDR, multidrug resistance; TAX, paclitaxel; DOX, doxorubicin; VCR, vincrinstine; 5-FU, 5-fluorouracil.
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f1-dddt-9-5301: CHB exerts anti-MDR activity in vitro.Notes: (A) Chemical structure of CHB; (B) average resistance factors of CHB and four reference agents.Abbreviations: CHB, chamaejasmin B; MDR, multidrug resistance; TAX, paclitaxel; DOX, doxorubicin; VCR, vincrinstine; 5-FU, 5-fluorouracil.

Mentions: CHB was kindly provided by Prof Hong Bin Xiao (China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China). CHB is a light gray powder with ≥99.0% purity, which enables its use in HPLC, and is prepared freshly by dissolving in dimethyl sulfoxide (DMSO; Amresco, Solon, OH, USA) before use. The final concentration of DMSO was 0.1% v/v. The chemical structure is shown in Figure 1A. Molecular formula is C32H26O10 and molecular weight is 570. Z-LEDH-FMK, a caspase 9 inhibitor, was purchased from BD Biosciences (San Jose, CA, USA). Paclitaxel (TAX), doxorubicin (DOX), vincrinstine (VCR), 5-fluorouracil (5-FU), 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenyformazan (MTT), and other chemicals were purchased from Sigma-Aldrich Co. (St Louis, MO, USA).


Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway.

Wang YJ, Li Q, Xiao HB, Li YJ, Yang Q, Kan XX, Chen Y, Liu XN, Weng XG, Chen X, Cai WY, Guo Y, Huang HF, Zhu XX - Drug Des Devel Ther (2015)

CHB exerts anti-MDR activity in vitro.Notes: (A) Chemical structure of CHB; (B) average resistance factors of CHB and four reference agents.Abbreviations: CHB, chamaejasmin B; MDR, multidrug resistance; TAX, paclitaxel; DOX, doxorubicin; VCR, vincrinstine; 5-FU, 5-fluorouracil.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590417&req=5

f1-dddt-9-5301: CHB exerts anti-MDR activity in vitro.Notes: (A) Chemical structure of CHB; (B) average resistance factors of CHB and four reference agents.Abbreviations: CHB, chamaejasmin B; MDR, multidrug resistance; TAX, paclitaxel; DOX, doxorubicin; VCR, vincrinstine; 5-FU, 5-fluorouracil.
Mentions: CHB was kindly provided by Prof Hong Bin Xiao (China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China). CHB is a light gray powder with ≥99.0% purity, which enables its use in HPLC, and is prepared freshly by dissolving in dimethyl sulfoxide (DMSO; Amresco, Solon, OH, USA) before use. The final concentration of DMSO was 0.1% v/v. The chemical structure is shown in Figure 1A. Molecular formula is C32H26O10 and molecular weight is 570. Z-LEDH-FMK, a caspase 9 inhibitor, was purchased from BD Biosciences (San Jose, CA, USA). Paclitaxel (TAX), doxorubicin (DOX), vincrinstine (VCR), 5-fluorouracil (5-FU), 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenyformazan (MTT), and other chemicals were purchased from Sigma-Aldrich Co. (St Louis, MO, USA).

Bottom Line: First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26.Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells.In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Capital Medical University, Beijing, People's Republic of China.

ABSTRACT
Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.

No MeSH data available.


Related in: MedlinePlus