p53 Contributes to the Chemotherapeutic Drug Doxorubicin-Induced Cell Death in Colorectal Cancer Cell Line HCT116

Doxorubicin is a commonly used chemotherapy drug for cancer treatment,although its effectiveness varies across different cancer types.p53 is a key factor involved in cell death induced by therapeutic agents,and it can be upregulated by doxorubicin,exhibiting a function of apoptosis.To further investigate the mechanism between p53 and doxorubicin,this study explored whether p53 plays a role in doxorubicin-induced cell death in the colorectal cancer line HCT116.The findings revealed that p53 was upregulated in HCT116 cells when treated with doxorubicin,and the knockdown of p53 decreased the sensitivity of HCT116 cells to doxorubicin.These results suggest that p53 plays an important role in doxorubicin-induced cell death in HCT116 cells,potentially contributing to more effective treatment approaches.

Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer

Nano-targeted delivery systems have been widely used for breast tumor drug delivery.Estrogen receptors are considered to be significant drug delivery target receptors due to their overexpression in a variety of tumor cells.However,targeted ligands have a significant impact on the safety and effectiveness of active delivery systems,limiting the clinical transformation of nanoparticles.Phytoestrogens have shown good biosafety characteristics and some affinity with the estrogen receptor.In the present study,molecular docking was used to select tanshinone IIA(Tan IIA)among phytoestrogens as a target ligand to be used in nanodelivery systems with somemodifications.Modified Tan IIA(Tan-NH2)showed a good biosafety profile and demonstrated tumor-targeting,anti-tumor and anti-tumor metastasis effects.Moreover,the ligand was utilized with the anti-tumor drug Dox-loaded mesoporous silica nanoparticles via chemical modification to generate a nanocomposite Tan-Dox-MSN.Tan-Dox-MSN had a uniform particle size,good dispersibility and high drug loading capacity.Validation experiments in vivo and in vitro showed that it also had a better targeting ability,anti-tumor effect and lower toxicity in normal organs.These results supported the idea that phytoestrogens with high affinity for the estrogen receptor could improve the therapeutic efficacy of nano-targeted delivery systems in breast tumors.

Targeted hyperalkalization with NaOH-loaded starch implants enhances doxorubicin efficacy in tumor treatment

High-alkali treatment using sodium hydroxide(NaOH)injection can be a therapeutic approach for killing tumor cells.Alkalization can damage cellular structures and lead to cell death.Increased alkalinity can also enhance the efficacy of certain chemotherapeutic drugs such as doxorubicin(DOX).In this study,NaOH-loaded starch implants(NST implants)were used to induce hyperalkalization(increase pH)in the tumor environment,thereby inducing necrosis and enhancing the effects of DOX.NaOH is a strongly alkaline substance that can increase the pH when injected into a tumor.However,the administration of NaOH can have toxic side effects because it increases the pH of the entire body,not just at the tumor site.To overcome this problem,we developed an injectable NST implant,in which NaOH can be delivered directly into the tumor.This study showed that NST implants could be easily administered intratumorally in mice bearing 4T1 tumors and that most of the NaOH released from the NST implants was delivered to the tumors.Although some NaOH from NST implants can be systemically absorbed,it is neutralized by the body’s buffering effect,thereby reducing the risk of toxicity.This study also confirmed both in vitro and in vivo that DOX is more effective at killing 4T1 cells when alkalized.It has been shown that administration of DOX after injection of an NST implant can kill most tumors.Systemic absorption and side effects can be reduced using an NST implant to deliver NaOH to the tumor.In addition,alkalinization induced by NST implants not only exerts anticancer effects but can also enhance the effect of DOX in killing cancer cells.Therefore,the combination of NaOH-loaded starch implants and DOX treatment has the potential to be a novel therapy for tumors.

Microwave ablation combined with transarterial chemoembolization containing doxorubicin hydrochloride liposome for treating primary and metastatic liver cancers

Aims:To determine the safety and efficacy of microwave ablation(MWA)and transarterial chemoembolization(TACE)with doxorubicin hydrochloride liposome(DHL)in patients with primary liver cancer(PLC)and metastatic liver cancer(MLC).Materials and methods:The medical records of patients with primary or metastatic liver cancer who underwent MWA combined with TACE containing DHL from March 2019 to March 2022 were collected and analyzed.Treatment-related adverse events(AEs)were recorded.Local tumor response was evaluated according to the modified RECIST criteria.Local tumor progression-free survival(LTPFS)and overall survival(OS)were calculated using the Kaplan-Meier method.Results:Altogether,96 patients with liver cancer were included(PLC,n=45;MLC,n=51).Forty(41.7%)patients experienced AEs during treatment,and eight(8.3%)patients developed grade 3 AEs.Compared to before treatment,the serum total bilirubin level and neutrophil to lymphocyte ratio significantly increased after treatment.The median LTPFS was 14.5 months in patients with PLC and 10.7 months in patients with MLC.The median OS was not reached in patients with PLC or MLC.The 1-month and 3-month disease control rates reached more than 80%in both groups.Conclusion:MWA combined with TACE with DHL may be a safe and effective method for the treatment of liver cancer.

Research progress on cardiotoxicity mechanism of doxorubicin and prevention and treatment of traditional Chinese medicine

Doxorubicin is an anthracycline antibiotic.As a broad-spectrum antitumor drug,it is widely used in clinic.However,doxorubicin is dose-dependent and shows obvious cardiotoxicity,which limits its clinical application.At present,the mechanism of doxorubicin induced cardiotoxicity has not been fully clarified.Reducing cardiotoxicity and improving the scope of clinical application have become the focus of research in recent years.This paper reviews the mechanism of doxorubicin cardiotoxicity and the prevention and treatment of doxorubicin cardiotoxicity with traditional Chinese medicine,in order to provide reference for the combined application of doxorubicin.

Nonclinical Study of the Active Components of Doxorubicin Hydrochloride Liposome Injection in Vivo

Objectives: A non-clinical study was performed to establish a LC-MS/MS method to determine the in vivo active components of doxorubicin hydrochloride liposome injection in the plasma of Sprague-Dawley rats. Methods: Ten male SD rats were administered tail vein with a single dose of 10 mg/kg, and the concentrations of doxorubicin hydrochloride in plasma, heart, liver, spleen, lung, and kidney were determined by liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated. Results: The final concentration of doxorubicin hydrochloride ranged from 500 ng/mL to 250,000 ng/mL, and the lower limit of quantification was 500 ng/mL;the main pharmacokinetic parameters: T1/2 was (19.282 ± 10.305) h, Cmax was (118514.828 ± 26155.134) ng/mL, AUC0-24 and AUC0-∞ were (1216659.205 ± 192706.268) ng/mL⋅h and (2082244.523 ± 860139.487) ng/mL⋅h, MRT0-24 and MRT0-∞ were (9.237 ± 0.423) h and (26.52 ± 14.015) h, respectively, and clearance (CL) was (0.005 ± 0.002) mL/h⋅ng. Conclusions: The method is simple, rapid, and sensitive, which can be used for the determination of doxorubicin hydrochloride concentration in the plasma of SD rats and pharmacokinetic non-clinical studies.

阿霉素脂质体导致的手足综合征研究进展

恶性肿瘤发病率逐年升高,新化疗药物在肿瘤临床的应用日益广泛,提高了抗肿瘤疗效的同时也出现了许多新的化疗不良反应,成为肿瘤临床难治的并发症。化疗药物引起的手足综合征（hand-foot syndrome,HFS）是目前肿瘤临床常见的不良反应,严重时影响肢体功能、导致痛性残疾,降低患者生活质量,还可能使有效的治疗被迫中断,间接影响患者的治疗获益[1,2]。

脂质体阿霉素和卡培他滨对老年转移性乳腺癌的疗效相当

至今，关于老年转移性乳腺癌（metastatic breast cancer，MBC）化疗药物的前瞻性数据仍然较少。近日，荷兰乳腺癌研究小组BOOG进行了一项多中心Ⅲ期OMEGA研究，比较脂质体阿霉素（pegylated liposomal Doxorubicin，PLD）与卡培他滨一线治疗≥65岁MBC患者的疗效和安全性。

DL1106与doxorubicin和paclitaxel协同作用及其机制研究

目的探讨DL1106与doxorubicin和paclitaxel对三阴性乳腺癌细胞协同作用效果及研究机制。方法将三阴性乳腺癌细胞MDA-MB-231和BT549分为4组,对照组,DL1106,DL1106+doxorubicin,DL1106+paclitaxel组作用24和48 h。用流式细胞仪检测细胞凋亡率和细胞周期;用JC-1检测细胞膜电位;用Caspase-Glo?3/7 assay检测细胞内胱天蛋白酶活性;用Western blotting检测细胞周期、细胞凋亡相关蛋白表达。采用si RNA技术敲低P53和PUMA的表达后检测药物联合对细胞的作用效果。结果与DL1106单独作用组细胞相比,DL1106与doxorubicin和paclitaxel联合作用组的细胞在48 h后凋亡率显著下降。DL1106与doxorubicin和paclitaxel联合作用导致细胞膜电位大幅下降并使细胞内胱天蛋白酶活性显著升高。同对照组相比,DL1106,DL1106+doxorubicin,DL1106+paclitaxel作用组的细胞均抑制MDM2的表达,促进P53和PUMA的表达。DL1106+doxorubicin,DL1106+paclitaxel协同作用抑制细胞Cyclin D1和Bcl-2的表达,促进BAX的表达。用P53si RNA和PUMA si RNA分别敲低细胞P53和PUMA的表达后,发现DL1106+doxorubicin,DL1106+paclitaxel联合作用效果明显减弱。结论 DL1106与doxorubicin和paclitaxel对三阴性乳腺癌细胞均具有协同作用,且这种协同作用通过P53/PUMA/BAX/caspase途径发挥作用。

Drug-eluting beads transarterial chemoembolization for hepatocellular carcinoma: Current state of the art

Transarterial chemoembolization(TACE) represents the current gold standard for hepatocellular carcinoma(HCC) patients in intermediate stage. Conventional TACE(c TACE) is performed with the injection of an emulsion of a chemotherapeutic drug with lipiodol into the artery feeding the tumoral nodules, followed by embolization of the same vessel to obtain a synergistic effect of drug cytotoxic activity and ischemia. Aim of this review is to summarize the main characteristics of drug-eluting beads(DEB)-TACE and the clinical results reported so far in the literature. A literature search was conducted using Pub Med until June 2017. In order to overcome the drawbacks of c TACE, namely lack of standardization and unpredictability of outcomes, non-absorbable embolic microspheres charged with cytotoxic agents(DEBs) have been developed. DEBs are able to simultaneously exert both the therapeutic components of TACE, either drug-carrier function and embolization, unlike c TACE in which applying the embolic agent is a second moment after drug injection. This way, risk of systemic drug release is minimal due to both high-affinity carrier activity of DEBs and absence of a time interval between injection and embolization. However, despite promising results of preliminary studies, clear evidence of superiority of DEB-TACE over c TACE is still lacking. A number of novel technical devices are actually in development in the field of loco-regional treatments for HCC, but only a few of them have entered the clinical arena. In absence of well-designed randomized-controlled trials, the decision on whether use DEB-TACE or c TACE is still controversial.

Experimental study on antitumor effect of arsenic trioxide in combination with cisplatin or doxorubicin on hepatocellular carcinoma

INTRODUCTIONThe main component of a traditional Chinese drug 'Pishuang'. arsenic trioxide (As2O3), has obviously selective anti-tumor effect on human hepatocellular carcinoma (HCC)in both in vitro and in vivo studies[1-5]. Due to limited effectiveness when any anti-carcinogen is used alone and obviously increased toxicity when the dose is raised, there is no exception for As2O3. Furthermore, combined chemotherapy contributes to improve therapeutic effectiveness, disperse toxicity and surmount drug-resistance,in which the combination of traditional Chinese and modern medicine has more advantages and characteristics. As a result,we made an experimental study on anti-tumor effect of As2O3in combination with cisplantin (PDD) or doxorubicin (ADM)on HCC. to investigate the possibility of AS2O3 in combination with PDD or ADM and nature of interaction between them,and to provide experimental basis for clinical application.

Malignant peritoneal mesothelioma

Malignant mesothelioma is a highly aggressive neoplasm.The incidence of malignant mesothelioma is increasing worldwide.Diffuse malignant peritoneal mesothelioma(DMPM) represents one-fourth of all mesotheliomas.Association of asbestos exposure with DMPM has been observed,especially in males.The great majority of patients present with abdominal pain and distension,caused by accumulation of tumors and ascitic ? uid.In the past,DMPM was considered a pre-terminal condition;therefore attracted little attention.Patients invariably died from their disease within a year.Recently,several prospective trials have demonstrated a median survival of 40 to 90 mo and 5-year survival of 30% to 60% after combined treatment using cytoreductive surgery and perioperative intraperitoneal chemotherapy.This remarkable improvement in survival has prompted new search into the medical science related to DMPM,a disease previously ignored as uninteresting.This review article focuses on the key advances in the epidemiology,diagnosis,staging,treatments and prognosis of DMPM that have occurred in the past decade.

A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy

Perioperative intraperitoneal chemotherapy in combination with cytoreductive surgery has been shown to be of benefit for treating selected patients with peritoneal surface malignancy.It has become a new standard of care in the management of diffuse malignant peritoneal mesothelioma and peritoneal dissemination of appendiceal malignancy.Numerous recent publications on carcinomatosis from colorectal cancer and gastric cancer identify groups of patients that would benef it from this local-regional approach for prevention and treatment of carcinomatosis.This review focuses on pharmacological information regarding intraperitoneal chemotherapeutic agents commonly used in gastrointestinal oncology.

MiR-34a overexpression enhances the inhibitory effect of doxorubicin on HepG2 cells

BACKGROUND Hepatocellular carcinoma(HCC) is the third leading cause of death from malignant tumors worldwide. More than 50% of HCC cases occur in China. The prognosis remains poor and overall efficacy is still unsatisfactory. Chemotherapy resistance is the most important reason for the poor outcome. Much progress has been made in the study of chemotherapy resistance of HCC;however, the specific mechanisms of progression of HCC have still only been partially established.Therefore, the mechanism of chemotherapy resistance in HCC requires more research.AIM To investigate the effect of miR-34 a expression on the growth inhibition of HepG2 cells by doxorubicin.METHODS A recombinant lentiviral vector containing miR-34 a was constructed and transfected into HepG2 cells. The expression of miR-34 a was detected by reverse transcription-polymerase chain reaction(commonly known as RT-PCR) before and after transfection. Cells were exposed to 2 μM doxorubicin or phosphatebuffered saline before and after transfection. Cell viability in each group was detected by MTT assay, and cell cycle and apoptosis were detected by flow cytometry. Changes in expression levels of phospho(p)-p53, sirtuin(SIRT) 1,cyclin D1, cyclin-dependent kinase(CDK) 4, CDK6, BCL-2, multidrug resistance protein(MDR) 1/P glycoprotein(P-gp), and AXL were detected by Western blotting.RESULTS Recombinant lentiviral vector LV-hsa-mir-34 a was successfully constructed by restriction endonuclease digestion and sequencing. RT-PCR showed that expression of miR-34 a in HepG2 cells was significantly upregulated after transfection(P < 0.01). MTT assay showed that growth of HepG2 cells was inhibited after upregulation of miR-34 a, and viability was significantly decreased after combined treatment with doxorubicin(P < 0.01). Flow cytometry showed that the number of HepG2 cells in G1 phase increased, and G1 phase arrest was more obvious after intervention with doxorubicin(P < 0.01). The apoptosis rate of HepG2 cells was increased after upregulation of miR-34 a, and became more obvious after intervention with doxorubicin(P < 0.01). Western blotting showed that upregulation of miR-34 a combined with treatment with doxorubicin caused significant changes in the expression levels of p-p53, SIRT1, cyclin D1, CDK4,CDK6, BCL-2, MDR1/P-gp and AXL proteins(P < 0.01).CONCLUSION MiR-34 a may enhance the inhibitory effect of doxorubicin by downregulating MDR1/P-gp and AXL, which may be related to p53 expression.

PEComa of the colon resistant to sirolimus but responsive to doxorubicin/ifosfamide

A 23-year-old male presented with a three-week-history of crampy abdominal pain and melaena.Colonoscopy revealed a friable mass filling the entire lumen of the cecum;histologically,it was classified as perivascular epithelioid cell tumor(PEComa).An magnetic resonance imaging scan showed,in addition to the primary tumor,two large mesenteric lymph node metastases and four metastatic lesions in the liver.The patient underwent right hemicolectomy and left hemihepatectomy combined with wedge resections of metastases in the right lobe of the liver,the resection status was R0.Subsequently,the patient was treated with sirolimus.After 4 mo of adjuvant mammalian target of rapamycin inhibition he developed two new liver metastases and a local pelvic recurrence.The visible tumor formations were again excised surgically,this time the resection status was R2 with regard to the pelvic recurrence.The patient was treated with 12 cycles of doxorubicin and ifosfamide under which the disease was stable for 9 mo.The clinical course was then determined by rapid tumor growth in the pelvic cavity.Second line chemotherapy with gemcitabine and docetaxel was ineffective,and the patient died 23 mo after the onset of disease.This case report adds evidence that,in malignant PEComa,the mainstay of treatment is curative surgery.If not achievable,the effects of adjuvant or palliative chemotherapy are unpredictable.

Melatonin and Doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines

AIM:To investigate whether Melatonin has synergistic effects with Doxorubicin in the growth-inhibition and apoptosis-induction of human hepatoma cell lines HepG2 and Bel-7402.METHODS:The synergism of Melatonin and Doxorubicin inhibited the cell growth and induced cell apoptosis in human hepatoma cell lines HepG2 and Bel-7402.Cell viability was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)assay.Cell apoptosis was evaluated using TUNEL method and flow cytometry.Apoptosis-related protein Bax,Bcl-2 and caspase-3 expressions were measured by immunohistochemical staining.RESULTS:Treatment with Melatonin(10 -8 -10 -5 mol/L) alone had a dose-related inhibitory effect on cell proliferation but no cytotoxic effect on hepatoma cell lines HepG2 and Bel-7402.Interestingly,when combined with Doxorubicin,Melatonin significantly increased the effects of cell growth inhibition and cell apoptosis.Furthermore,TUNEL staining and flow cytometry revealed that cooperative apoptosis induction was associated with decreased expression of Bcl-2 as well as increased expression of Bax and Caspase3.CONCLUSION:The synergism of Melatonin and Doxorubicin inhibits hepatoma cell growth and induces cell apoptosis.

Hesperidin as a preventive resistance agent in MCF-7 breast cancer cells line resistance to doxorubicin

Objective:To evaluate of hesperidin to overcome resistance of doxorubicin in MCF-7 resistant doxorubicin cells(MCF-7/Dox)in cytotoxicity apoptosis and P-glycoprotein(Pgp)expression in combination with doxorubicin.Methods:The cytotoxic properties.50%inhibition concentration(IC_(50))and its combination with doxorubicin in MCF-7 cell lines resistant to doxorubicin(MCF-7/Dox)cells were determined using MTT assay.Apoptosis induction was examined by double staining assay using ethidium bromide-acridine orange.Immunocytochemistry assay was performed to determine the level and localization of Pgp.Results:Single treatment of hesperidin showed cytotoxic activity on MCF-7/Dox cells with IC_(50)value of 11μmol/L.Thus,combination treatment from hesperidin and doxorubicin showed addictive and antagonist effect(CI>1.0).Hesperidin did not increase the apoptotic induction,but decreased the Pgp expressions level when combined with doxorubicin in low concentration.Conclusions:Hesperidin has cytotoxic effect on MCF-7/Dox cells with IC_(50)of 11μmol/L.Hesperidin did not increased the apoptotic induction combined with doxorubicin.Cochemotherapy application of doxorubicin and hesperidin on MCF-7/Dox cells showed synergism effect through inhibition of Pgp expression.

Transcatheter arterial chemoembolization with a fine-powder formulation of cisplatin for hepatocellular carcinoma

AIM:To evaluate the efficacy of transcatheter arterial chemoembolization(TACE) using a suspension of a fine-powder formulation of cisplatin(DDPH) for hepatocellular carcinoma(HCC).METHODS:The study population was comprised of 164 patients who were treated by TACE alone.Of these patients,76 underwent TACE using a suspension of DDPH in lipiodol(LPD)(DDPH group),and the remaining 88 underwent TACE with an emulsion of doxorubicin(ADM) with LPD(ADM group).We compared the DDPH group with the ADM group in terms of the objective early response rate,progression free survival(PFS) and overall survival(OS).RESULTS:The objective early response rate in the DDPH group was significantly higher than that in the ADM group(54% vs 24%,P < 0.001).The PFS rate in the DDPH group was also significantly higher than that in the ADM group(P < 0.001).Moreover,the OS in the DDPH group was significantly longer than that in the ADM group(P = 0.002).Although the incidence rate of nausea or vomiting in the DDPH group was higher than that in the ADM group,the ADM group showed a higher incidence rate of the adverse events of hepatic arterial damage and leucopenia.No other serious complications were observed in either group.CONCLUSION:We conclude that TACE using a suspension of DDPH in LPD could be a useful treatment for HCC.

Preparation and evaluation of poly(L-histidine) based pH-sensitive micelles for intracellular delivery of doxorubicin against MCF-7/ADR cells

In this study, a p H-sensitive micelle self-assembled from poly(L-histidine) based triblock copolymers of poly(ethylene glycol)–poly(D,L-lactide)–poly(L-histidine)(mPEG-PLA-PHis) was prepared and used as the intracellular doxorubicin(Dox) delivery for cancer chemotherapy. Dox was loaded into the micelles by thin-film hydration method and a Box–Behnken design for three factors at three levels was used to optimize the preparations. The optimized mPEG-PLA-Phis/Dox micelles exhibited good encapsulation efficiency of 91.12%,a mean diameter of 45 nm and narrow size distribution with polydispersity index of 0.256.In vitro drug release studies demonstrated that Dox was released from the micelles in a p Hdependent manner. Furthermore, the cellular evaluation of Dox loaded micelles displayed that the micelles possessed high antitumor activity in vitro with an IC50 of 35.30 μg/ml against MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments indicated that m PEG-PLA-Phis micelles mediated efficient cytoplasmic delivery of Dox with the aid of poly(Lhistidine) mediated endosomal escape. In addition, blank m PEG-PLA-Phis micelles were shown to be nontoxic to MCF-7/ADR cells even at a high concentration of 200 μg/ml. The pHsensitive mPEG-PLA-PHis micelles have been demonstrated to be a promising nanosystem for the intracellular delivery of Dox for MDR reversal.

Characterization and in vitro release studies of oral microbeads containing thiolated pectin–doxorubicin conjugates for colorectal cancer treatment

Novel oral microbeads were developed based on a biopolymer–drug conjugate of doxorubicin(DOX) conjugated with thiolated pectin via reducible disulfide bonds. The microbeads were fabricated by ionotropic gelation with cations such as Al3+, Ca2+ and Zn2+. The results showed that using zinc acetate can produce the strongest microbeads with spherical shape.However, the microbeads prepared from thiolated pectin–DOX conjugate were very soft and irregular in shape. To produce more spherical microbeads with suitable strength, the native pectin was then added to the formulations. The particle size of the microbeads ranged from 0.87 to 1.14 mm. The morphology of the microbeads was characterized by optical and scanning electron microscopy. DOX was still in crystalline form when used in preparing the microbeads, as confirmed by powder X-ray diffractometry. Drug release profiles showed that the microbeads containing thiolated pectin–DOX conjugate exhibited reduction-responsive character;in reducing environments, the thiolated pectin–DOX conjugate could uncouple resulting from a cleavage of the disulfide linkers and consequently release the DOX. The best-fit release kinetics of the microbeads containing thiolated pectin–DOX conjugate, in the medium without reducing agent, fit the Korsmeyer–Peppas model while those in the medium with reducing agent fit a zero-order release model. These results suggested that the microbeads containing thiolated pectin–DOX conjugate may be a promising platform for cancer-targeted delivery of DOX, exploiting the reducing environment typically found in tumors.