Multidrug-resistant Tumor Research Articles

Knockout of P-glycoprotein abolish the collateral sensitivity of CHORC5 multidrug resistant cells

Multidrug resistant tumor cells show collaterally sensitive to a range of non-toxic drugs. In this report, we describe the isolation of several P-glycoprotein-knockout cell clones, using CRISPR/Cas9, from Chinese hamster multidrug resistant model cell line and its parental cells (e.g., CHORC5 and AuxB1, respectively). All three P-glycoprotein-knockout clones of CHORC5 cells show complete loss of resistance to anti-cancer drugs (e.g., colchicine and doxorubicin), while gaining resistance to well characterized collateral sensitivity drugs (e.g., verapamil, progesterone and NSC73306). A correlation between P-glycoprotein and Sorcin expression levels and a possible role for the latter in low grade resistance to colchicine and doxorubicin was observed. Furthermore, we show that P-glycoprotein expression is necessary for the ROS-mediated mechanism of collateral sensitivity. However, expectantly, P-glycoprotein-knockout clones of CHORC5 cells revealed a dramatic increase in the accumulation of Rhodamine 123, Mito tracker red and doxorubicin, but not Hoechst 33342. The latter findings and their significance to P-glycoprotein collateral sensitivity remain to be determined.

Oncolytic peptide nanomachine circumvents chemo resistance of renal cell carcinoma

Due to intrinsic and acquired chemo/radiotherapy-resistance, renal cell carcinoma shows limited therapeutic response to clinically utilized targeting drugs. Here a tumor-activated oncolytic peptide nanomachine is devised to selectively lysing tumor cell membrane without causing drug resistance. Specifically, in the acidic tumor microenvironment, the oncolytic peptide nanomachine automatically activated through morphologically transformation from nanoparticles to nanofibrils with restoring α-helical conformation, which physically bind to tumor cell membrane with multiple (spatially correlated and time-resolved) interactions and subsequently lyse local cell membrane. The IC50 of the oncolytic peptide nanomachine is as low as 2.44 μM and it inhibit up to 90% of tumor cells within 2 h with unique bystander killing effect. In vivo, the tumor inhibition rate of the oncolytic peptide nanomachine is 71% without off-target activity and hemolytic activity. These results support that tumor-selective oncolytic peptide nanomachine represent a promising alternative approach for multidrug-resistant tumor treatments by inducing cell membrane lysis.

BAG family proteins contributes to autophagy-mediated multidrug resistance of tumor.

Multidrug resistance (MDR) is a significant cause of tumor treatment failure. Accumulating evidence suggests that autophagy plays a significant role in the development of MDR. Autophagy is a conserved mechanism that maintains tumor homeostasis by removing damaged mitochondria. However, the specific regulatory mechanism is unclear. Here, we summarize recent studies on the role of autophagy in the development of MDR and the initiation of mitophagy by Bcl-2-associated athanogene (BAG) family proteins. Additionally, this mini-review emphasizes the regulatory role of BAG family proteins, which maintain mitochondrial homeostasis by regulating the PINK1/Parkin pathway. Elucidation of the regulatory mechanisms of mitophagy may foster the development of clinical therapeutic strategies for MDR tumors.

Infigratinib (BGJ 398), a Pan-FGFR Inhibitor, Targets P-Glycoprotein and Increases Chemotherapeutic-Induced Mortality of Multidrug-Resistant Tumor Cells.

The microtubule-targeting agents (MTAs) are well-known chemotherapeutic agents commonly used for therapy of a broad spectrum of human malignancies, exhibiting epithelial origin, including breast, lung, and prostate cancer. Despite the impressive response rates shortly after initiation of MTA-based therapy, the vast majority of human malignancies develop resistance to MTAs due to the different mechanisms. Here, we report that infigratinib (BGJ 398), a potent FGFR1-4 inhibitor, restores sensitivity of a broad spectrum of ABCB1-overexpressing cancer cells to certain chemotherapeutic agents, including paclitaxel (PTX) and doxorubicin (Dox). This was evidenced for the triple-negative breast cancer (TNBC), and gastrointestinal stromal tumor (GIST) cell lines, as well. Indeed, when MDR-overexpressing cancer cells were treated with a combination of BGJ 398 and PTX (or Dox), we observed a significant increase of apoptosis which was evidenced by an increased expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin V-positive cells, as well. Moreover, BGJ 398 used in combination with PTX significantly decreased the viability and proliferation of the resistant cancer cells. As expected, no apoptosis was found in ABCB1-overexpressing cancer cells treated with PTX, Dox, or BGJ 398 alone. Inhibition of FGFR-signaling by BGJ 398 was evidenced by the decreased expression of phosphorylated (i.e., activated) forms of FGFR and FRS-2, a well-known adaptor protein of FGFR signaling, and downstream signaling molecules (e.g., STAT-1, -3, and S6). In contrast, expression of MDR-related ABC-transporters did not change after BGJ 398 treatment, thereby suggesting an impaired function of MDR-related ABC-transporters. By using the fluorescent-labeled chemotherapeutic agent PTX-Alexa488 (Flutax-2) and doxorubicin, exhibiting an intrinsic fluorescence, we found that BGJ 398 substantially impairs their efflux from MDR-overexpressing TNBC cells. Moreover, the efflux of Calcein AM, a well-known substrate for ABCB1, was also significantly impaired in BGJ 398-treated cancer cells, thereby suggesting the ABCB1 as a novel molecular target for BGJ 398. Of note, PD 173074, a potent FGFR1 and VEGFR2 inhibitor failed to retain chemotherapeutic agents inside ABCB1-overexpressing cells. This was consistent with the inability of PD 173074 to sensitize Tx-R cancer cells to PTX and Dox. Collectively, we show here for the first time that BGJ 398 reverses the sensitivity of MDR-overexpressing cancer cells to certain chemotherapeutic agents due to inhibition of their efflux from cancer cells via ABCB1-mediated mechanism.

Discussion on the Structural Modification and Anti-tumor Activity of Flavonoids.

Flavonoids are secondary metabolites of plants. In general，most flavonoids are combined with glucosides and have extremely complex molecular structures. In nature, these flavonoids have a variety of biological activities, such as anti-oxidation，anti-virus, anti-tumor, scavenging free radicals, etc.; however，due to poor solubility and stability of flavonoids，their bioavailability is limited. The drug design method is used to modify the structure of flavonoids to give them special properties. At present, flavonoids have shown broad application prospects in treating tumors, inhibiting proliferation, migration, invasion, angiogenesis, and multi-drug resistance of tumors and have become a research hotspot.

Two-Pronged Anti-Tumor Therapy by a New Polymer-Paclitaxel Conjugate Micelle with an Anti-Multidrug Resistance Effect.

IntroductionCancerous tumors are still a major disease that threatens human life, with tumor multidrug resistance (MDR) being one of the main reasons for the failure of chemotherapy. Thus, reversing tumor MDR has become a research focus of medical scientists.MethodsHere, a reduction-sensitive polymer prodrug micelle, mPEG-DCA-SS-PTX (PDSP), was manufactured with a new polymer inhibitor of drug resistance as a carrier to overcome MDR and improve the anti-tumor effect of PTX.ResultsThe PDSP micelles display good stability, double-responsive drug release, and excellent biocompatibility. The PDSP micelles reduced the cytotoxicity of PTX to normal HL-7702 cells and enhanced that to SMMC-7721 and MCF-7 cells in vitro. Improved sensitivity of A549/ADR to PDSP was also observed in vitro. Furthermore, in vivo experiments show reduced systemic toxicity and enhanced therapeutic efficacy of PTX to H22 subcutaneous tumor-bearing mice.ConclusionThis work proves that the reduction-sensitive polymer prodrug micelles carried by the new polymer inhibitor can be used as an alternative delivery system to target tumors and reverse MDR for paclitaxel and other tumor-resistant drugs.

Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells.

Paclitaxel resistance is a challenging factor in chemotherapy resulting in poor prognosis and cancer recurrence. Signal transducer and activator of transcription factor 3 (STAT3), a key transcription factor, performs a critical role in cancer development, cell survival and chemoresistance, while its inactivation overwhelms drug resistance in numerous cancer types including lung cancer. Additionally, the fucosyltransferase 4 (FUT4) is a crucial enzyme in post-translational modification of cell-surface proteins involved in various pathological conditions such as tumor multidrug resistance (MDR). The P-glycoprotein (P-GP) is the well-known ABC transporter member that imparts drug resistance in different cancer types, most notably paclitaxel resistance in lung cancer cells. LncRNA-MALAT1 exerts a functional role in the cancer development as well as the drug resistance and is linked with STAT3 activation and activity of FUT4. Moreover, STAT3-mediated induction of P-GP is well-documented. Natural compounds of Sesquiterpene Lactone (SL) family are well-known for their anticancer properties with particular emphasis over STAT3 inhibitory capabilities. In this study, we explored the positive correlation of MALAT1 with STAT3 and FUT4 activity in paclitaxel resistant A549 (A549/T) lung cancer cells. Additionally, we investigated the anticancer activity of two well-known members of SLs, alantolactone (ALT) and Brevilin A (Brv-A), in A549/T lung cancer cells. ALT and Brv-A induced apoptosis in A549/T cells. Furthermore, these two natural SLs suppressed MALAT1 expression, STAT3 activation, and FUT4 and P-GP expression which are the hallmarks for paclitaxel resistance in A549 lung cancer cells. The inhibition of MALAT1 enhanced the competence of these SLs members significantly, which accounted for the growth inhibition as well as anti-migratory and anti-invasive effects of ALT and Brv-A. These findings suggest SLs to be the promising agents for overcoming paclitaxel resistance in A549 lung cancer cells.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Multipotent Poly(Tertiary Amine-Oxide) Micelles for Efficient Cancer Drug Delivery.

The cancer drug delivery process involves a series of biological barriers, which require the nanomedicine to exhibit different, even opposite properties for high therapeutic efficacy. The prevailing design philosophy, i.e., integrating these properties within one nanomedicine via on‐demand property transitions such as PEGylation/dePEGylation, complicates nanomedicines’ composition and thus impedes clinical translation. Here, polyzwitterionic micelles of poly(tertiary amine‐oxide)‐block‐poly(ε‐caprolactone) (PTAO‐PCL) amphiphiles that enable all the required functions are presented. The zwitterionic nature and unique cell membrane affinity confer the PTAO micelles long blood circulation, efficient tumor accumulation and penetration, and fast cellular internalization. The mitochondrial targeting capability allows drug delivery into the mitochondria to induce mitochondrial dysfunction and overcome tumor multidrug resistance. As a result, the PTAO/drug micelles exhibit potent anticancer efficacy. This simple yet multipotent carrier system holds great promise as a generic platform for potential clinical translation.

Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles

The emergence of multidrug resistance (MDR) in tumors leads to reduced chemotherapeutic efficacy, and P-glycoprotein (P-gp) overexpression is one of the main causes of MDR. In previous reports, we demonstrated that a variety of hederagenin (HD) derivatives could reverse MDR in tumors in vivo and in vitro. To further enrich the structure types, enhance the activity, and improve the structure–activity relationships (SARs), three series of HD derivatives were designed and synthesized in this study via A-ring fusion and innovative utilization of the structural advantages of nitrogen-containing heterocycles and benzyl group substitution. We evaluated the MDR reversal activity of 21 HD derivatives in KBV (multidrug-resistant oral epidermoid carcinoma) cells and refined their SARs. The results of cell experiments illustrated that more than half of the compounds had MDR reversal activity. Among them, compound 16 displayed relatively stronger MDR reversal ability, as it improved the sensitivity of KBV cells to paclitaxel, vincristine, mitoxantrone and cisplatin with IC50 values of 3.19, 0.65, 125.30, and 4.54 nM, respectively. The results of mechanistic analysis demonstrated that compound 16 inhibited the efflux function of P-gp by activating P-gp ATPase and increased the accumulation of rhodamine 123 in KBV cells. Importantly, the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice was enhanced by compound 16 based on the growth suppression rate of 56.24%. These results indicated that introducing nitrogen-containing heterocycles could effectively improve the MDR reversal activity of HD derivatives, which appear to be promising lead compounds for tumor MDR reversal agent development.

A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer.

Lacking nano-systems for precisely codelivering the chemotherapeutics paclitaxel (PTX) and the natural P-glycoprotein (P-gp) inhibitor, quercetin (QU), into cancer cells and controlling their intracellular release extremely decreased the anticancer effects in multidrug resistant (MDR) tumors. To overcome this hurdle, we constructed hybrid polymeric nanoparticles (PNPs) which consist of redox-sensitive PTX/polyethyleneimine-tocopherol hydrogen succinate-dithioglycollic acid PNPs and pH-sensitive hyaluronic acid-QU conjugates. The obtained hybrid PNPs can be internalized into drug-resistant breast cancer cells by the hyaluronic acid/CD44-mediated endocytosis pathway and escape from the lysosome through the “proton sponge effect”. Under the trigger of intracellular stimuli, the nanoplatform used the pH/glutathione dual-sensitive disassembly to release QU and PTX. The PTX diffused into microtubules to induce tumor cell apoptosis, while QU promoted PTX retention by down-regulating P-gp expression. Moreover, tocopherol hydrogen succinate and QU disturbed mitochondrial functions by generating excessive reactive oxygen species, decreasing the mitochondrial membrane potential, and releasing cytochrome c into the cytosol which consequently achieved intracellular multilevel chemotherapy amplification in MDR cancers. Importantly, the PNPs substantially suppressed tumors growth with an average volume 2.54-fold lower than that of the control group in the MCF-7/ADR tumor-bearing nude mice model. These presented PNPs would provide a valuable reference for the coadministration of natural compounds and anticarcinogens for satisfactory combination therapy in MDR cancers.

Recent Progress of Novel Nanotechnology Challenging the Multidrug Resistance of Cancer.

Multidrug resistance (MDR) of tumors is one of the clinical direct reasons for chemotherapy failure. MDR directly leads to tumor recurrence and metastasis, with extremely grievous mortality. Engineering a novel nano-delivery system for the treatment of MDR tumors has become an important part of nanotechnology. Herein, this review will take those different mechanisms of MDR as the classification standards and systematically summarize the advances in nanotechnology targeting different mechanisms of MDR in recent years. However, it still needs to be seriously considered that there are still some thorny problems in the application of the nano-delivery system against MDR tumors, including the excessive utilization of carrier materials, low drug-loading capacity, relatively narrow targeting mechanism, and so on. It is hoped that through the continuous development of nanotechnology, nano-delivery systems with more universal uses and a simpler preparation process can be obtained, for achieving the goal of defeating cancer MDR and accelerating clinical transformation.

Study of Allosteric Transitions of Human P-Glycoprotein by Using the Two-State Anisotropic Network Model.

Human P-glycoprotein (P-gp) is a kind of ATP-binding cassette (ABC) transporters. Once human P-gp is overexpressed in tumor cells, which can lead to tumor multidrug resistance (MDR). However, the present experimental methods are difficult to obtain the large-scale conformational transition process of human P-gp. In this work, we explored the allosteric pathway of human P-gp from the inward-facing (IF) to the outward-facing (OF) state in the substrate transport process with the two-state anisotropic network model (tANM). These results suggest that the allosteric transitions proceed in a coupled way. The conformational changes of nucleotide-binding domains (NBDs) finally make the transmembrane domains (TMDs) to the OF state via the role of the allosteric propagation of the intracellular helices IH1 and IH2. Additionally, this allosteric pathway is advantageous in energy compared with other methods. This study reveals the conformational transition of P-gp, which contributes to an understanding of the allosteric mechanism of ABC exporters.

IMB5476, a novel microtubule inhibitor, induces mitotic catastrophe and overcomes multidrug resistance in tumors

IMB5046 is a nitrobenzoate microtubule inhibitor we reported previously. During screening of its structural analogues, we identified a novel compound IMB5476 with increased aqueous solubility. Here, its antitumor activity and the underlying mechanism were investigated. IMB5476 disrupted microtubule networks in cells and arrested cell cycle at G2/M phase. It inhibited purified tubulin polymerization in vitro. Competition assay indicated that it bound to tubulin at the colchicine pocket. Further experiments proved that it induced cell death by mitotic catastrophe and apoptosis. Notably, it was a poor substrate of P-glycoprotein and exhibited potent cytotoxicity against drug-resistant tumor cells. In addition, IMB5476 could inhibit angiogenesis in vitro. IMB5476 also inhibited the growth of drug-resistant KBV200 xenografts in mice. Conclusively, our data reveal a novel nitrobenzoate microtubule inhibitor with improved aqueous solubility and can overcome multidrug resistance.

Research Progress and Prospects of Autophagy in the Mechanism of Multidrug Resistance in Tumors.

Although the treatment of cancer has made great strides in clinical practice, its high morbidity and fatality rates remain a major threat to human health. Multidrug resistance (MDR) often appears in the process of tumor treatment, leading to tumor refractory and aggravating the risk of tumor recurrence. Therefore, antitumor MDR plays a key role in tumor chemotherapy. Autophagy is an important process for the turnover of intracellular materials, which is commonly seen in the treatment of sensitive and multidrug-resistant tumors, and it can play different roles in various types of MDR tumor cells and tissues. Autophagy plays a dual regulatory role in MDR tumors. On the one hand, autophagy can promote the formation of MDR in tumor cells, weaken the killing effect of chemotherapy drugs on tumor cells, and play a protective role in tumor survival. On the other hand, autophagy production in the cellular environment can kill MDR tumor cells, reverse tumor resistance and enhance the efficiency of chemotherapy drugs. Therefore, the regulation of autophagy to overcome MDR has become increasingly significant in tumor chemotherapy. In this article, we discussed and summarized the research progress of autophagy in MDR tumors, mainly involving the different characteristics of autophagy in MDR cancer cells.

Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)-conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.

Indolicidin revisited: biological activity, potential applications and perspectives of an antimicrobial peptide not yet fully explored.

The emergence of multidrug-resistant bacteria, viruses and tumors is a serious threat to public health. Among natural peptides, indolicidin, a 13-residue peptide belonging to the cathelicidin family, deserves special attention. Indolicidin has a broad spectrum of biological activity and is active against a wide range of targets, such as bacteria (Gram+ and Gram-), fungi and viruses. Here, we review the most important features of the biological activity, potential applications and perspectives of indolicidin and its analogs. Although not yet approved for commercialization, this peptide has great potential to be applied in different areas, including the medical, biomedical, food industry and other unexplored areas. To achieve this goal, a multidisciplinary team of researchers must work together to fine tune peptides that overall lead to novel analogs and formulations to combat existing and possibly future diseases.

Expression of the Stem Cell Marker ABCB5 in Normal and Tumor Tissues.

The ATP-binding cassette subfamily B member 5 (ABCB5) transporter plays a pivotal role in melanocyte progenitor cell fusion and has been identified as a tumor-initiating cell marker. In this study, we determined ABCB5 expression in normal tissues among various species, i.e., Homo sapiens, Mus musculus (mouse), Rattus norvegicus (rat), Sus scrofa domesticus (pig), Gallus gallus (chicken), Anser anser (goose), Poecilia reticulata (Guppy fish), and Lumbricus terrestris (earthworm), as well as 426 biopsies of different human tumor types (colorectal, cervical, endometrium, vaginal, nasopharyngeal, kidney, breast, colon, prostate, pancreas, lung, gallbladder, bladder, brain, liver, skin, small intestine, testis, tonsil, uterus, thyroid, stomach, esophagus, fallopian, parotid, and ovary). Using immunohistochemical staining, ABCB5 expression was detected and evaluated in formalin-fixed, paraffin-embedded sections. High ABCB5 expression was found in normal tissues in specialized cells with secretory and excretory functions, chorionic villi of the placenta, hepatocytes, and blood-tissue barrier sites in the brain and testis. Besides, heterogeneous expression of ABCB5 was also observed in many different tumor types derived from breast, endometrium, ovary, uterus, cervix, prostate, lung, brain, colon, liver, nasopharynx, and others. The localization of ABCB5 in different normal tissues suggests that this protein has an excretory pumping role for physiological metabolites and xenobiotics. This physiological role highlighted its possible impact on the development of multidrug resistance in tumors. Further studies are required to establish the possible clinical significance of ABCB5 as a predictive marker for drug resistance and as a prognostic marker for patient survival.

Preparation of Sorafenib tosylate self-emulsified drug delivery system and the effect on combination therapy with Bosutinib against HCT116/SW1417 cells

The Sorafenib tosylate (ST) emulsified drug delivery system (ST-SEDDS) was designed and characterized in response to the poor solubility and bioavailability of ST. ST-SEDDS formed fine emulsions with a mean diameter of 158.3 ± 1.4 nm, a narrow size distribution (PDI 0.257), and a Zeta potential of –22.41 ± 1.2 mV after being diluted with 5% glucose. The cytotoxicity of ST- SEDDS against HCT116 and HCT116/SW1417 cells was comparable to that of free ST, with HCT116/SW1417 cells having a half maximal inhibitory concentration of 175 µg/mL. ST-SEDDS in combination with Bosutinib was used to achieve a satisfactory inhibitory effect on HCT116/SW1417 cells. With a combined index of 0.68, the combination of ST-SEDDS and Bosutinib had a superior synergistic effect. And the combination group's cellular uptake of Bosutinib by HCT116/SW1417 cells was significantly higher than the Bosutinib treatment groups. It meant that ST- SEDDS increased HCT116/SW1417 cells' Bosutinib uptake. Finally, SEDDS was a promising alternative formulation for Sorafenib tosylate (ST). Combining ST-SEDDS and Bosutinib for a synergistic effect appears to be a promising strategy for improving antitumor efficacy against HCT116/SW1417 and other multidrug-resistant tumours.

A self-amplified ROS-responsive chemodrug-inhibitor conjugate for multi-drug resistance tumor therapy.

P-glycoprotein (P-gp) induced multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy. The combined delivery of chemodrug and P-gp inhibitor is a promising pathway to reverse MDR. However, the intrinsic stimuli in the tumor microenvironment could not realize a complete drug release, which would induce poor cancer therapeutic efficacy. Herein, we conjugated tamoxifen (TAM) with D-α-tocopherol polyethylene glycol1000 succinate (TPGS) based on a reactive oxygen species (ROS)-responsive aryl boronic ester bond to construct a self-amplified ROS-responsive chemodrug-inhibitor (TPGS-TAM) co-delivery system. Due to its amphiphilic property, the TPGS-TAM conjugates could self-assemble into uniform spherical nanoparticles (NPs). After effective endocytosis by cancer cells, the intracellular ROS cleaved the aryl boronic ester bond and initiated the release of TAM and α-tocopherol succinate (α-TOS) from the NPs. Subsequently, the released α-TOS further generated ROS to facilitate the release of TAM. Moreover, α-TOS also consumed adenosine triphosphate (ATP) to impair ATP-dependent P-gp mediated drug efflux to reverse the tumor's drug resistance. As a result, the TPGS-TAM NPs enhanced the antitumor effect with a tumor inhibition rate (TIR) high up to 74.6 ± 6.1% in an MCF-7/ADR tumor model. Based on systematic in vitro and in vivo assessments, this self-amplified ROS-responsive carrier-free conjugate of chemodrug/P-gp inhibitor may shed light on the potential application for the MDR cancer therapy.