Polyphyllin I combined with doxorubicin shows chemosensitization effect in vivo and reduces immunotoxicity of doxorubicin

Zhu Xiang,Na Xin,Zeng Yueqin,Xu Yangantai,Chai Dongya,Yang Huanzhi,Miao Jingqian,Zhang Yuan,Yang Fenghua,Wang Yuehu,Zhou Yiping 대한독성 유전단백체 학회 2022 Molecular & cellular toxicology Vol.18 No.3

Background Polyphyllin I (PPI), a steroidal saponin, exhibits antitumor activity and chemosensitization effect for a broad spectrum of cancer cells, however, its toxicity and chemosensitization effect in vivo is still unknown. Objective We investigated PPI’s cytotoxic activity, toxicity and chemosensitization effect and in vitro and in vivo . Results The IC 50 values of PPI on MCF-7, H22, and S180 tumor cells were 4.37 μmol/L, 1.71 μmol/L, and 0.92 μmol/L, respectively. The LD 50 of PPI was found to be 47.9 mg/kg using ip. injection. PPI at concentrations of 0.3 mg/kg, 0.6 mg/ kg, 1.2 mg/kg, and 2.4 mg/kg (1/80 LD 50 –1/20 LD 50 ) were synergized with DOX of 0.5 mg/kg to inhibit the H22 and S180 tumor growth in vivo by inducing apoptosis without obvious immunotoxicity. PPI exhibited a remarkable hemolytic effect on rabbit erythrocytes (EC 50 = 4.3 μM), while it had no impact in mice. Conclusion Our study revealed that the PPI-sensitized chemotherapeutic effect, when used in safe doses, circumvents immunotoxic side effects of DOX in vivo; thus, helping future clinical research.

Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery

Lee, Jae-Young,Termsarasab, Ubonvan,Lee, Mee Yeon,Kim, Dong-Hwan,Lee, Song Yi,Kim, Jung Sun,Cho, Hyun-Jong,Kim, Dae-Duk Elsevier Science B.V. Amsterdam 2017 ACTA BIOMATERIALIA Vol. No.

<P><B>Abstract</B></P> <P>A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone <I>via</I> amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX=10:1 [w/w]) NPs with <75nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The <I>in vitro</I> cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. <I>In vivo</I> pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy.</P> <P><B>Statement of Significance</B></P> <P>Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites

Alcantara, L.M.,Kim, J.,Moraes, C.B.,Franco, C.H.,Franzoi, K.D.,Lee, S.,Freitas-Junior, L.H.,Ayong, L.S. Academic Press 2013 Experimental parasitology Vol.134 No.2

Members of the ATP-binding cassette (ABC)-type transporter superfamily have been implicated in multidrug resistance in malaria, and various mechanistic models have been postulated to explain their interaction with diverse antimalarial drugs. To gain insight into the pharmacological benefits of inhibiting ABC-type transporters in malaria chemotherapy, we investigated the in vitro chemosensitization potential of various P-glycoprotein inhibitors. A fluorescent chloroquine derivative was synthesized and used to assess the efflux dynamics of chloroquine in MDR and wild type Plasmodium falciparum parasites. This novel BODIPY-based probe accumulated in the digestive vacuole (DV) of CQ-sensitive parasites but less so in MDR cells. Pre-exposure of the MDR parasites to non-cytocidal concentrations of unlabeled chloroquine resulted in a diffused cytoplasmic retention of the probe whereas a similar treatment with the CQR-reversing agent, chlorpheniramine, resulted in DV accumulation. A diffused cytoplasmic distribution of the probe was also obtained following treatment with the P-gp specific inhibitors zosuquidar and tariquidar, whereas treatments with the tyrosine kinase inhibitors gefitinib or imatinib produced a partial accumulation within the DV. Isobologram analyses of the interactions between these inhibitors and the antimalarial drugs chloroquine, mefloquine, and artemisinin revealed distinct patterns of drug synergism, additivity and antagonism. Taken together, the data indicate that competitive tyrosine kinase and noncompetitive P-glycoprotein ATPase-specific inhibitors represent two new classes of chemosensitizing agents in malaria parasites, but caution against the indiscriminate use of these agents in antimalarial drug combinations.

8-Hydrocalamenene, Derived from Reynoutria elliptica, Suppresses Constitutive STAT3 Activation, Inhibiting Proliferation and Enhancing Chemosensitization of Human Multiple Myeloma Cells

남동우,송준호,김성무,Shu Yuan Chiang,김지성,정원석,장형진,정상훈,나영순,김성훈,심범상,안광석 한국식품영양과학회 2014 Journal of medicinal food Vol.17 No.3

The identification of the active compounds of herbal medicines and the molecular targets of those compounds is an attractive therapeutic objective. Reynoutria elliptica has been used for the treatment of various inflammatory diseases as a Korean folk remedy. Based on the evidence that anti-inflammatory agents frequently exert antiproliferative activity, we tested two sesquiterpene derivatives, 8-hydrocalamenene (HC) and 8,14-dihydrocalamenene (DHC), for their ability to induce apoptosis and suppress signal transducer and activator of transcription 3 (STAT3) activation in multiple myeloma (MM) U266 cells. We found that HC inhibited cell viability in U266, but not in peripheral blood mononuclear cells. HC exerted significant cytotoxicity and induced substantial subG1-phase arrest and apoptosis as compared with DHC. HC inhibited the expression of gene products involved in antiapoptosis (Bcl-2 and Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9), all of which are known to be regulated by STAT3. Furthermore, HC up-regulated cyclin-dependent kinase inhibitor p21 and induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. Interestingly, HC blocked constitutive STAT3 activation through the inhibition of activation of upstream kinases Janus-like kinase 1 ( JAK1), JAK2, and c-Src and up-regulated PIAS3. Deletion of STAT3 reversed cytotoxic effects and the down-regulation of cyclin D1 and c-myc by HC in MM cells. Finally, this sesquiterpene significantly synergized the cytotoxic and apoptotic effects of bortezomib in U266 cells. Taken together, these results suggest that HC is a novel blocker of STAT3 activation which may have a potential in the prevention and treatment of MM.

Expression of DNA-dependent Protein Kinase and Its Relationship with Epidermal Growth Factor Receptor Signaling in Metastatic Cancer Cell Lines

황지영,김선희,강치덕,윤만수,Hwang Jee Young,Kim Sun Hee,Kang Chi Dug,Yoon Man Soo Korean Society of Life Science 2005 생명과학회지 Vol.15 No.3

암세포의 유전적 불안정성은 부적절하게 활성화된 DNA수복경로와 관련되어 있다. 전이성 암은 높은 유전적 불안정성을 나타내는데, 이와 관련하여 본 연구에서는 전이성 암세포에서의 중요한 DNA수복 단백질의 하나인 DN의존성 단백질 키나아제(DNA-PK)의 발현 변화를 조사하였다. 여러 종류의 전이도가 다른 암세포들을 대상으로 한 실험에서 전이성 암세포들은 각각의 모세포에 비하여 DNA-PK 성분의 조절 소단위인 Ku70/80의 발현 및 Ku의 DNA 결합 활성이 증강되어 있었다. 또한 DNA-PK의 촉매 소단위인 DNA-PKcs의 발현 및 whole DNA-PK복합체의 kinase의 활성도 전이도가 큰 암세포에서 그 모세포보다 증강되어 있음을 알 수 있어, 전이성 암세포의 증강된 DNA수복능은 부적절한 DNA수복을 일으켜 암의 진행 및 전이를 촉진시키는 원인이 될 수 있음을 시사하였다. 한편 암세포의 표피성장인자수용체의 신호전달의 증강은 암의 침윤과 전이에 관련되어 있으며, DNA-PK의 기 기능에도 영향을 줄 수 있는 가능성이 보고 된 바 있는데, 본 연구에서는 표피성장인자수용체의 신호전달과 DNA-PK의 관련성을 명확히 밝히기 위하여 새로 개발된 EGFR tyrosine kinase inhibitor인 PKI166의 DNA-PK의 활성에 미치는 영향을 조사하였다. PKI166는 Ku70/80 및 DNA-PKcs의 발현을 억제하였고 이와 관련하여 전이성 및 항암제 다제내성 암세포에서 PKI166에 의하여 항암제에 대한 감수성을 증가시켜 항암제 내성을 나타내는 전이성 암세포 대한 치료법 연구에 DNA-PK가 분자적 표적이 될 수 있음을 밝혔다. The genetic instability of cancer cells may be related to inappropriately activated DNA repair pathways. In present study, the modulated expression of DNA-dependent protein kinase (DNA-PK), a major DNA repair protein, in human cancer metastatic cells was tested. The expressions of Ku70/80, regulatory subunit of DNA-PK, and the Ku DNA-binding activity in various highly metastatic cell lines were higher than those in each parental cell line. Also, the expression of DNA-PKcs, catalytic subunit of DNA-PK, and the kinase activity of the whole DNA-PK complex in highly metastatic cells were significantly increased as compared to those of parental cells, suggesting that the enhanced DNA repair capacity of metastatic cells could be associated with aberrant use of DNA repair, which may mediate tumor progression and metastatic potential. Increased EGFR (epidermal growth factor receptor) signaling has been associated with tumor invasion and metastasis, and the linkage between EGFR-mediated signaling and DNA-PK has been suggested. This study showed that PKI166, the new EGFR tyrosine kinase inhibitor, modulated the expressions of Ku70/80 and DNA-PKcs and also revealed the chemosensitization effect of PKI166 against metastatic cells may be in part due to inhibition of Ku70/80. These results suggest that interference in EGFR signaling by EGFR inhibitor resulted in the impairment of DNA repair activity, and thus DNA-PK could be possible molecular targets for therapy against metastatic cancer cells.

$I{\kappa}B{\alpha}$-SR 유전자이입이 Cisplatin, Paclitaxel에 대한 폐암세포주의 감수성에 미치는 영향

이석영,설자영,박경호,박근민,황용일,김철현,장승훈,권성연,유철규,김영환,한성구,심영수,이춘택,Lee, Seok-Young,Seol, Ja-Young,Park, Kyung-Ho,Park, Gun-Min,Hwang, Yong-Il,Kim, Cheol-Hyeon,Jang, Seung-Hun,Kwon, Sung-Youn,Yoo, Chul-Gyu,Kim, Young 대한결핵및호흡기학회 2001 Tuberculosis and Respiratory Diseases Vol.51 No.2

연구배경 : 종양 세포들이 항암제에 대하여 저항을 나타내는 기전인 'apoptosis에 대한 저항'에 NF-${\kappa}B$의 활성이 중요한 역할을 하리라 생각되고 있다. 즉, NF-${\kappa}B$가 종양세포의 apoptosis를 억제하는 작용을 일으킴으로써 종양 세포의 생존에 유리하게 작용하고 있음이 제시되 고 있다. 방 법 : 본 연구에서는 비소세포폐암에 대한 항암 치료의 내성에 대하여 외부 자극으로 분해되지 않는 $I{\kappa}B{\alpha}$-SR의 삽입으로 NF-${\kappa}B$의 활성을 억제시키고 이로 인해 항암제에 대한 폐암세포주의 감수성이 증가하는지 여부를 밝혀 보고자 하였다. 결 과 : 비소세포폐암 세포주로 NCI H157, NCI H460 세포주를 이용하였고, Ad-$I{\kappa}B{\alpha}$-SR를 transduction 한 후 cisplatin을 처치한 군에서 NF-${\kappa}B$의 핵 내로의 이동이 억제되었으며 대조군과 비교시 $IC_{50}$이 2-3배 정도 유의하게 낮아짐을 관찰하였다. 또한 paclitaxel의 경우에도 Ad-$I{\kappa}B{\alpha}$-SR로 감염된 폐암세포주는 대조군과 비교시 IC50이 2배 정도 유의하게 낮아짐을 관찰하였다. 이러한 항암제에 대한 감수성의 증가의 기전으로 cisplatin의 경우는 $I{\kappa}B{\alpha}$-SR의 이입이 NF-${\kappa}B$의 활성을 억제 함으로 인한 apoptosis의 증대 때문인 것으로보인다. 결 론 : 폐암세포주에서 Ad-$I{\kappa}B{\alpha}$-SR transduction은 Clsplatin, paclitaxel에 대한 폐암세포주의 감수성을 증가시킴으로 앞으로 폐암을 치료하는데 있어 새로운 치료 방법이 될 수 있을 것으로 보인다. Background : Some chemotherapeutic drugs induce NF-${\kappa}B$ activation by degrading the $I{\kappa}B{\alpha}$ protein in cancer cells which contributes to anticancer drug resistance. We hypothesized that inhibiting $I{\kappa}B{\alpha}$ degradation would block NF-${\kappa}B$ activation and result in increased tumor cell mortality in response to chemotherapy. Methods : The "superrepressor" form of the NF-${\kappa}B$ inhibitor was transferred by an adenoviral vector (Ad-$I{\kappa}B{\alpha}$-SR) to the human lung cancer cell lines (NCI H157 and NCI H460). With a MIT assay, the level of sensitization to cisplatin and paclitaxel were measured. To confirm the mechanism, an EMSA and Annexin V assay were performed. Results : EMSA showed that $I{\kappa}B{\alpha}$-SR effectively blocked the NF-${\kappa}B$ activation induced by cisplatin. Transduction with Ad-$I{\kappa}B{\alpha}$-SR resulted in an increased sensitivity of the lung cancer cell lines to cisplatin and paclitaxel by a factor of 2~3 in terms of $IC_{50}$. Annexin-V analysis suggests that this increment in chemosensitivity to cisplatin probably occurs through the induction of apoptosis. Conclusion : The blockade of chemotherapeutics induced NF-${\kappa}B$ activation by inducing Ad-$I{\kappa}B{\alpha}$-SR, increased apoptosis and increasing the chemosensitivity of the lung cancer cell lines tested, subsequently. Gene transfer of $I{\kappa}B{\alpha}$-SR appears to be a new therapeutic strategy of chemosensitization in lung cancer.

Potential of a Small Molecule Inhibitor in the Sensitization of Pancreatic Cancer Cells to Gemcitabine

( Subash Gupta ),( Anusmita Shekher ),( Nikee Awasthee ),( Ankit Srivastava ) 대한간학회 2024 춘·추계 학술대회 (The Liver Week) Vol.2024 No.1

Carnosol: A Phenolic Diterpene With Cancer Chemopreventive Potential

전경수,Juthika Kundu,채인경,Kundu, Joydeb Kumar 대한암예방학회 2014 Journal of cancer prevention Vol.19 No.2

Cancer is an unbeaten health challenge for the humankind. After striving for decades to find a cancer cure, attention has now been shifted to reduce the morbidity and mortality from cancer by halting the course of tumor development. Numerous bioactive phytochemicals, especially those present in edible and non-edible plant species, have been reported to reduce the risk of many cancers. Multiple lines of evidence suggest that carnosol, a phenolic diterpene present in rosemary (Rosmarinus officinalis L.), holds the promise of preventing certain types of cancer. A remarkable progress has been made in delineating the biochemical mechanisms underlying the chemopreventive effects of carnosol. Results from in vitro cell culture studies as well as animal model experiments have revealed that carnosol inhibits experimentally induced carcinogenesis and exhibits potent anti-oxidative, anti-inflammatory, antiproliferative and apoptosis inducing properties. Moreover, carnosol enhances the sensitivity of chemoresistant cancer cells to chemotherapeutic agents. The purpose of this review is to shed light on the detailed mechanistic aspects of cancer chemoprevention with carnosol.

Characteristic Features of Cytotoxic Activity of Flavonoids on Human Cervical Cancer Cells

Sak, Katrin Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.19

Cervical cancer is the most common gynecologic malignancy worldwide and development of new therapeutic strategies and anticancer agents is an urgent priority. Plants have remained an important source in the search for novel cytotoxic compounds and several polyphenolic flavonoids possess antitumor properties. In this review article, data about potential anticarcinogenic activity of common natural flavonoids on various human cervical cancer cell lines are compiled and analyzed showing perspectives for the use of these secondary metabolites in the treatment of cervical carcinoma as well as in the development of novel chemotherapeutic drugs. Such anticancer effects of flavonoids seem to differentially depend on the cellular type and origin of cervical carcinoma creating possibilities for specific targeting in the future. Besides the cytotoxic activity per se, several flavonoids can also contribute to the increase in efficacy of conventional therapies rendering tumor cells more sensitive to standard chemotherapeutics and irradiation. Although the current knowledge is still rather scarce and further studies are certainly needed, it is clear that natural flavonoids may have a great potential to benefit cervical cancer patients.

Combination of nitric oxide and drug delivery systems: tools for overcoming drug resistance in chemotherapy

Kim, J.,Yung, B.C.,Kim, W.J.,Chen, X. Elsevier Science Publishers 2017 Journal of controlled release Vol.263 No.-

<P>Chemotherapeutic drugs havemade significant contributions to anticancer therapy, along with other therapeutic methods including surgery and radiotherapy over the past century. However, multidrug resistance (MDR) of cancer cells has remained as a significant obstacle in the achievement of efficient chemotherapy. Recently, there has been increasing evidence for the potential function of nitric oxide (NO) to overcomeMDR. NO is an endogenous and biocompatible molecule, contrasting with other potentially toxic chemosensitizing agents that reverse MDR effects, which has raised expectations in the development of efficient therapeutics with low side effects. In particular, nanoparticle-based drug delivery systems not only facilitate the delivery of multiple therapeutic agents, but also help bypass MDR pathways, which are conducive for the efficient delivery of NO and anticancer drugs, simultaneously. Therefore, this review will discuss the mechanism of NO in overcoming MDR and recent progress of combined NO and drug delivery systems. Published by Elsevier B. V.</P>