| Objective:Cancer is one of the most serious diseases to human health. Chemotherapy with catatonic drug is the most preferred treatment for solid tumors and hematological neoplasms. However, chemotherapeutic drugs always causes toxic side effects such as vomiting, bone marrow suppression, etc. more seriously, aqquired drug resistance by tumor during chemotherapy leads to faiure for cancer treatment, which is the the main cause of death in cancer patients. Chemosensitizers are themselves non-toxic or low toxic to tumors, but can enhance antitumor activity of antitumor agents when they are coadministered with antitumor agents. In other words, a chemosensitizer can help an antitumor drug to achieve better efficacy at lower dosages which are less toxic to normal tissues. Therefore, many studies focus on this topic in order to find a highly effective chemosensitizer that can be clinically used for treatment of cancer. In our previous study we found that the AcOEt extract of Marsdenia Tenacissima (W-t) showed ability to increase growth inhibitory effect of paclitaxol to tumor cells. Further separation of W-t provided several steroidal compounds (W-1,W-3,W-7,W-9, W-10).In this study, effects of these components on increasing paclitaxel activity had been studied both in votro and in vivo.Methods:(1) In vitro study:In human oral epidermoid carcinoma cell line KB-3-1and its drug-resistant sub line KBV1, human cervical carcinoma cell line HeLa, human colon adenocarcinoma cell line HCT-15, Human nasopharyngeal carcinoma cell line CNE and human leukemia cell line K562, cytotoxic effects of paclitaxel used alone or in combination with certain concentrations of w-t, w-1, w-3, w-7, w-9, or w-10were investigated by MTT assay or CCK-8assay (K562). Ability of these components to decrease IC50values of paclitaxel (concentration to inhibit50%of cell growth) had been compared.(2) In vivo study:In solid tumor models established by subcutaneously injection of KB-3-1, HeLa and HCT-15cells to the back of female BALB/c nude mice, paclitaxel had been given alone or in combination with W-t, W-1, W-3or W-9. Tumor volumes had been measured. Ability of W-t and relative components to enhance growth inhibitory effect of paclitaxel to tumors were assessed by comparing tumor volumes in mice treated with paclitaxcel alone (Va) to that in mice treated with paclitaxel combined with a W-t component(Vc). the more smaller the Vc, the more effective the chemosensitizer.Results:1. W-t, W-1, W-3, W-7, W-9or W-10showed no significant cytotoxicity to HeLa, HCT-15, KBV1, CNE and K562cells, IC50values at48h of exposure to W-t were greater than140μg/mL, and to the others were greater than100μM. IC50values at48h of exposure to paclitaxel in HeLa, HCT-15, KB-3-1, KBV1, CNE and K562cells were0.039±0.025μg/mL,0.38±0.15μg/mL,0.006±0.002μg/mL,11.00±3.13μg/mL,0.02±0.021μg/mL,0.005±0.002μg/mL, respectively.2. In the presence of10μg/mL of W-t, IC50values of paclitaxel to above cells were0.022±0.012μg/mL,0.04±0.005μg/mL,0.006±0.002,3.67±2.51μg/mL,0.015±0.009μg/mL,0.004±0.002μg/mL. W-t increased cytotoxicity of paclitaxel to HCT-15, HeLa and KBV1cells.3. In the presence of10μM of W-3, W-7or W-9; The IC50values of paclitaxel in HeLa, HCT-15and KBV1cells were0.02±0.01μg/mL,0.05±0.02μg/mL, and1.24±0.68μg/mL, for W-3,0.008±0.003μg/mL,0.02±0.02μg/mL, and1.09 ±1.76μg/mL for W-7,0.007±0.001μg/mL,0.02±0.02μg/mL and1.15±1.13μg/mL for W-9, respectively. W-3, W-7and W-9reduced IC50values of taxol in HELA, HCT-15and KBV1cells.4. W-1and W-10showed no effect on increasing paclitaxel toxicityto tumor cells tested.5. In KB-3-1solid tumor models, administration of W-t (100mg/kg/d, i.g.), W-3(50mg/kg/d, i.p.) or W-9(20mg/kg/d, i. p.) did not inhibit tumor growth during a10-d treatment period. But when they were coadministered with5doses of paclitaxel (10mg/kg, i. p., every other day), tumor growth rates were significanltly slowed down when compared to that in mice treated with paclitaxcel alone. W-t, W-3and W-9enhanced growth inhibitory effect of paclitaxel on KB-3-1tumors.6. In HeLa solid tumor models, administration of W-t (100mg/kg/d, i.g.) or W-3(50mg/kg/d, i.p.) did not inhibit tumor growth during a10-d treatment period. But when they were coadministered with5doses of paclitaxel (10mg/kg, i.p., every other day), tumor growth rates were significanltly slowed down when compared to that in mice treated with paclitaxcel alone. W-t and W-3enhanced growth inhibitory effect of paclitaxel on HeLa tumors.7. In HCT-15solid tumor models, administration of W-3(50mg/kg/d, i.p.) did not inhibit tumor growth during a10-d treatment period. But when they were coadministered with5doses of paclitaxel (10mg/kg, i. p., every other day), tumor growth rates were significanltly slowed down when compared to that in mice treated with paclitaxcel alone. W-3enhanced growth inhibitory effect of paclitaxel on HCT-15tumors.8. W-1had also been investigated in HeLa and HCT-15tumor models but exhibited no activity in enhancing inhibitory effect on tumor growth.Conclusion:W-t, W-3and W-9remarkably increased growth inhibitory effect of paclitaxel both in vitro and in vivo, showing to be prmising candidates as sensitizers for paclitaxel in clinical treatment of tumors. |
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