Protein synthesis inhibitors can suppress the development of thermotolerance in tumor tissues on repeated heating. Withaferin A (WA), isolated from Withania somnifera has cytotoxic and inhibitory action on protein synthesis. In the present investigation, effect of WA on development and decay of thermotolerance in B16F1 melanoma was studied in C57BL mice. Tumors of 10010 mm3 size were subjected to repeated hyperthermia (HT) at 43°C for 30 minutes. WA was injected after first hyperthermia treatment. The tumor response was assessed by calculating the tumor growth delay (GD). The GD increased with increase in time gap between two hyperthermia treatments and was significantly higher (p < 0.05 to p < 0.001) in WA treated groups at all the respective time gaps (except at 0h and 120h) compared to hyperthermia alone group. WA increases the tumor response during repeated hyperthermia by reducing the magnitude of thermotolerance developed and by decreasing the recovery time from thermotolerance.
Urano M.Kinetics of thermotolerance in normal and tumor tissue: a review. Cancer Res. 1986;46:474-482.
2.
Gerner EW, Schneider MJInduced thermal resistance in HeLa cells. Nature. 1975;256:500-502.
3.
Uma Devi P.Withania somnifera Dunal (ashwagandha): potential plant source of a promising drug for cancer chemotherapy and radiosensitization. Indian J Exp Biol.1996;34:927-932.
4.
Dhalla NS, Sastry MS, Malhotra CLChemical studies of the leaves of Withania somnifera. J Pharm Sci. 1961;50:876-877.
5.
Sethi PD, Subramanian SSAnti-inflammatory and anti-arthritic activity of withanolides. Indian J Pharmacol. 1972;4:30-31.
6.
Shohat B., Joshua H.Effect of Withaferin A on Ehrlich ascites tumor cells. II. Target tumor cell destruction in vivo by immune activation. Int J Cancer.1971;8:487-496.
7.
Uma Devi P., Akagi K., Ostapenko V., Tanaka Y., Sugahara T.Withaferin A, a new radiosensitizer from the Indian medicinal plant, Withania somnifera. Int J Radiat Biol. 1996 ;69:193-197.
8.
Uma Devi P., Kamath R., Rao BSS.Radiosensitization of a mouse melanoma by Withaferin A: in vivo studies . Indian J Exp Biol. 2000;38:432-435.
9.
Kupchan SM, Doskotch RW, Bollinger P., McPhaile AT, Sim GA, Renauld JAS.The isolation and structural elucidation of a novel steroidal tumor inhibitor from Acnitus arborescens. J Am Chem Soc. 1965 ;87:5805-5806.
10.
Shohat B.Antimitotic properties of Withaferin A in tissue culture. Harefuah. 1972;83:582-583.
11.
Chowdhary K. , Neogy RKMode of action of Withaferin A and withanolide D. Biochem Pharmacol. 1975 ;24:919-920.
12.
Fuska J., FuskovaA., Rosazza JP, NicholasAWNovel cytotoxic and antitumor agents. IV. Withaferin A: relation of its structure to the in vitro cytotoxic effects on P388 cells. Neoplasia.1984;31: 31-36.
13.
Henle KJ, Leeper DBModification of the heat response and thermotolerance by cyclohexamide, hydroxyurea and lucanthone in CHO cells. Radiat Res. 1982 ;90:339-347.
14.
Li GC, Laszlo A.Amino acid analogs while inducing heat shock protein sensitize CHO cells to thermal damage. J Cell Phys. 1985 ;122:91-97.
15.
Uma Devi P. , Rao BSS.Response of mouse sarcoma-180 to bleomycin in combination with radiation and hyperthermia. Strahlenther Onkol. 1993;10:601-607.
16.
Uma Devi P., Guruprasad K.Influence of clamping-induced ischemia and reperfusion on the response of a mouse melanoma to radiation and hyperthermia. Int J Hyperthermia . 2001;17: 357-367.
17.
Subramanian SS , Sethi PDWithaferin A from Withania coagulans roots . Curr Sci (India). 1969;38:267-268.
18.
Sharada AC, Solomon FE, Uma Devi P., Srinivasan KK, Udupa N.Withaferin A and plubagain: isolation and acute toxicity studies. Amala Res Bull (India). 1993;13:20-23.
19.
Suffness M., Douros J.Drugs of plant origin. In: De Vita VT , Bush S, eds. Methods in Cancer Research. Vol 16. New York, NY: Academic Press. 1979:79.
20.
Mooibrek J., Dikomey E., Zywietz F., Jung H.Thermotolerance kinetics and growth rate changes in the R1H tumor heated at 43°C. Int J Hyperthermia. 1988;4:677-686.
21.
Rofstad EK, Wahl A., Tveit KM, Monge OR, Brustad T.Survival curves after X-ray and heat treatments for melanoma cells derived directly from surgical specimens of tumors in man. Radiother Oncol. 1985;4:33-44.
22.
WestraA,Dewey WCHeat shock during the cell cycle of Chinese hamster cells in vitro . Int J Radiat Biol. 1971;19:467-477.
23.
Henle KJ, Leeper DBInteraction of hyperthermia and radiation in CHO cells: recovery kinetics . Radiat Res. 1976;66: 505-518.
24.
JungH.,DikomeyE.,ZyweitzF.Ausma_undzeitlicheEntwicklung der Thermotoleranz und deren Einflu_ auf die Strahlenem findichkeit von soliden Transplantations tumoren. In: Streffer C, Herbst M, Schwabe H, eds. Lokale Hyperthermie. Köln, Germany: Deutscher Aertz Verlag. 1986:23-28.
25.
Kaneko R., Hayashi Y., Tohnai L., Ueda M., Ohtsuka K.Hsp40, a possible indicator of thermotolerance of murine tumor in vivo. Int J Hyperthermia. 1997;13:507-516.
26.
Hu Q., Kavanagh M-C., Newcombe D., Hill RPDetection of hypoxic fractions in murine tumors by comet assay: comparison with other techniques. Radiat Res. 1995;144:266-275.
27.
Landry J., Bermier D., Chretien P., et al. Synthesis and degradation of heat shock proteins during development and decay of thermotolerance. Cancer Res. 1982;42:2457-2461.
28.
Yokota S., Kitahara M., Nagata K.Benzylidene lactam compound, KNK-437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells. Cancer Res. 2000;60:2942-2948.
29.
Koishi M., Yokota S., Mae T., et al. The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo. Clin Cancer Res. 2001;7:215-219.
30.
Shibuya K., Kawasaki S., Kuroda M., Asaumi J., Hiraki Y.Inhibition of thermotolerance observed on tSAF8 cells. Int J Hyperthermia. 2000;16:449-456.
31.
Hosokawa N. , Hirayoshi K., Kudo H., et al. Inhibition of the activation of the heat shock factor in vivo and in vitro by flavonoids . Mol Cell Biol. 1992;12:3490-3498.
32.
Wei YQ, Zhao X., Kariya Y., Teshigawara K., Uchida A.Induction of apoptosis by quercetin: involvement of heat shock protein . Cancer Res. 1994;54:4952-4957.
