Retinoic acid and evernyl-based menadione-triazole hybrid cooperate to induce differentiation of neuroblastoma cells.

Neuroblastoma arises when immature neural precursor cells do not mature into specialized cells. Although retinoic acid (RA), a pro-differentiation agent, improves the survival of low-grade neuroblastoma, resistance to retinoic acid is found in high-grade neuroblastoma patients. Histone deacetylases (HDAC) inhibitors induce differentiation and arrest the growth of cancer cells; however, HDAC inhibitors are FDA-approved mostly for liquid tumors. Therefore, combining histone deacetylase (HDAC) inhibitors and retinoic acid can be explored as a strategy to trigger the differentiation of neuroblastoma cells and to overcome resistance to retinoic acid. Based on this rationale, in this study, we linked evernyl group and menadione-triazole motifs to synthesize evernyl-based menadione-triazole hybrids and asked if the hybrids cooperate with retinoic acid to trigger the differentiation of neuroblastoma cells. To answer this question, we treated neuroblastoma cells using evernyl-based menadione-triazole hybrids (6a-6i) or RA or both and examined the differentiation of neuroblastoma cells. Among the hybrids, we found that compound 6b inhibits class-I HDAC activity, induces differentiation, and RA co-treatments increase 6b-induced differentiation of neuroblastoma cells. In addition, 6b reduces cell proliferation, induces expression of differentiation-specific microRNAs leading to N-Myc downregulation, and RA co-treatments enhance the 6b-induced effects. We observed that 6b and RA trigger a switch from glycolysis to oxidative phosphorylation, maintain mitochondrial polarization, and increase oxygen consumption rate. We conclude that in evernyl-based menadione-triazole hybrid, 6b cooperates with RA to induce differentiation of neuroblastoma cells. Based on our results, we suggest that combining RA and 6b can be pursued as therapy for neuroblastoma. Schematic representation of RA and 6b in inducing differentiation of neuroblastoma cells.

Diaryl ether derivative inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells.

Papillary thyroid carcinoma contributes to about 80% of the total thyroid cancer cases. BRAFV600E is a frequently occurring mutation in PTCs. Although several BRAF inhibitors are available, many thyroid cancer patients acquire resistance to BRAF inhibitors. Therefore, new targets and drugs need to be identified as therapies. Ferroptosis is a recently discovered type of cell death, and inhibiting glutathione peroxidase 4 (GPX4) using small molecules was found to trigger ferroptosis. But it is unknown whether inhibiting GPX4 renders thyroid cancer cells susceptible to ferroptosis. To identify novel GPX4 inhibitors, we focused on our previously reported cohort of diaryl ether and dibenzoxepine molecules. In this study, we asked whether diaryl ether and dibenzoxepine derivatives trigger ferroptosis in thyroid cancer cells. To answer this question, we screened diaryl ether and dibenzoxepine derivatives in cell-based assays and performed mechanism of action studies. We found that a diaryl ether derivative, 16 decreased thyroid cell proliferation and triggered ferroptosis by inhibiting GPX4 expression levels. Molecular modeling and dynamics simulations showed that 16 binds to the active site of GPX4. Upon deciphering the mode of 16-induced ferroptosis, we found that 16 treatments decrease mitochondrial polarization and reduce mitochondrial respiration similar to a ferroptosis inducer, RSL3. We conclude that the diaryl ether derivative, 16 inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells. Based on our observations, we suggest that 16 can be lead-optimized and developed as a ferroptosis-inducing agent to treat thyroid cancers.

Prohibitin1 maintains mitochondrial quality in isoproterenol-induced cardiac hypertrophy in H9C2 cells.

BACKGROUND INFORMATION: Various types of stress initially induce a state of cardiac hypertrophy (CH) in the heart. But, persistent escalation of cardiac stress leads to progression from an adaptive physiological to a maladaptive pathological state. So, elucidating molecular mechanisms that can attenuate CH is imperative in developing cardiac therapies. Previously, we showed that Prohibitin1 (PHB1) has a protective role in CH-induced oxidative stress. Nevertheless, it is unclear how PHB1, a mitochondrial protein, has a protective role in CH. Therefore, we hypothesized that PHB1 maintains mitochondrial quality in CH. To test this hypothesis, we used Isoproterenol (ISO) to induce CH in H9C2 cells overexpressing PHB1 and elucidated mitochondrial quality control pathways. RESULTS: We found that overexpressing PHB1 attenuates ISO-induced CH and restores mitochondrial morphology in H9C2 cells. In addition, PHB1 blocks the pro-hypertrophic IGF1R/AKT pathway and restores the mitochondrial membrane polarization in ISO-treated cells. We observed that overexpressing PHB1 promotes mitochondrial biogenesis, improves mitochondrial respiratory capacity, and triggers mitophagy. CONCLUSION: We conclude that PHB1 maintains mitochondrial quality in ISO-induced CH in H9C2 cells. SIGNIFICANCE: Based on our results, we suggest that small molecules that induce PHB1 in cardiac cells may prove beneficial in developing cardiac therapies.

Anticancer effect and apoptosis induction by azaflavanone derivative in human prostate cancer cells.

Polyphenols are naturally occurring organic compounds with varying structures represented by four major groups: flavonoids, phenolic acids, lignans and stilbenes. Several studies suggested that these secondary metabolites have health benefits due to its anti-tumorigenic effect. Therefore, substantial effort has been put forward to isolate and characterize these natural compounds and synthesize analogues that may serve as potential anti-cancer therapeutics. This present study is aimed at designing and synthesis of azaflavanone derivative and in understanding its mechanism of action in vitro and in vivo. Molecular docking studies predicted that the compound can potentially bind strongly to the Cyclin E1-Cdk2 complex which is a key mediator of the cell cycle progression indicating a biological interference in aggressive prostate cancer. Further downstream studies to understand its cytotoxicity and mechanism of action showed this azaflavanone derivative markedly inhibits viability of prostate cancer cells (DU145) showing an IC50 value of 0.4 µM compared to other cancer cells. The pharmacological ROS insult using the azaflavanone derivative increases the oxidative damage leading to high expression of apoptotic markers with increasing concentration. On compound treatment, the cells lose the metabolic flexibility accompanied by mitochondrial dysfunction leading to cell cycle arrest and apoptosis. Further, no compound mediated toxicity was observed in xenograft mouse model of prostate cancer at a concentration as high as 5 mg/kg. The tumor burden was reduced to 60% rendering the azaflavanone derivative a potential candidate in cancer therapeutics. Collectively, the compound triggers cell cycle arrest and ROS mediated oxidative stress sensitizing the cancerous cells towards apoptosis.

Downregulation of BORIS/CTCFL leads to ROS-dependent cellular senescence and drug sensitivity in MYCN-amplified neuroblastoma.

Brother of Regulator of Imprinted Sites (BORIS) or CCCTC-binding factor like (CTCFL) is a nucleotide-binding protein, aberrantly expressed in various malignancies. Expression of BORIS has been found to be associated with the expression of oncogenes which regulate the reactive oxygen species (ROS) biogenesis, DNA double-strand break repair, regulation of stemness, and induction of cellular senescence. In the present study, we have analyzed the effects of knockdown of BORIS, a potential oncogene, on the induction of senescence and tumor suppression. Loss of BORIS downregulated the expression of critical oncogenes such as BMI1, Akt, MYCN, and STAT3, whereas overexpression increased their respective expression levels in MYCN-amplified neuroblastoma cells. BORIS knockdown exhibited high levels of ROS biogenesis, indicating an upregulated mitochondrial superoxide production and thereby induction of senescence. Our study also showed that the loss of BORIS facilitated cellular senescence through the disruption of telomere integrity via altering the expression of various proteins required for telomere capping (POT1, TRF2, and TIN1). In addition to affecting ROS production and DNA damage, BORIS knockdown sensitized the cells toward chemotherapeutic drugs and induced apoptosis. Tumor induction studies on in vivo xenograft mouse models showed that cells with loss of BORIS/CTCFL failed to induce tumors. From our study, we conclude that silencing BORIS/CTCFL influences tumor growth and proliferation by regulating key oncogenes. The results also indicated that the BORIS knockdown can cause cellular senescence and upon a combinatorial treatment with chemotherapeutic drugs can induce enhanced drug sensitivity in MYCN-amplified neuroblastoma cells.

Inhibitory role of oleanolic acid and esculetin in HeLa cells involve multiple signaling pathways.

The global burden of cervical cancer from low and middle-income groups is increasing at alarming rates with more than half a million women being diagnosed every year. Although the disease is largely preventable when screened and diagnosed in earlier stages, the development of resistance and relapse had resulted in a poor prognosis. Therefore, a comprehensive approach needs to be put forward to understand and develop new preventive and therapeutic strategies to effectively combat cancer. Recently, much attention has been diverted to plant-derivatives for the treatment as they exhibit potent anti-cancer properties and side-effects caused by chemotherapeutic agents can also be prevented. Oleanolic acid and Esculetin are natural compounds known for their anti-cancer properties. Hence, the present study investigates the effect and mechanism of these compounds on cervical carcinoma, using HeLa cells. Posttreatment, it was observed that these compounds inhibited proliferation by both arresting the cells in the sub G1 phase and inducing senescence. Also, a marked reduction in the migration and cell survival was observed, as evidenced by results obtained from wound healing assay and Annexin V-FITC/PI staining. Furthermore, studies on the expression pattern of genes involved in major signaling pathways demonstrated a profound effect of these compounds. Taken together, the results of our study suggest that both Oleanolic acid and esculetin serve as a plausible therapeutic agent.

Synthesis of some novel methyl ß-orsellinate based 3, 5-disubstituted isoxazoles and their anti-proliferative activity: Identification of potent leads active against MCF-7 breast cancer cell.

A series of sixteen novel methyl ß-orsellinate based 3, 5-disubstituted isoxazole hybrids (3-18) were synthesized in excellent yields by employing 1,3-dipolar cycloaddition reaction of terminal alkyne and corresponding nitriloxides as the key step. The structures of all the synthesized compounds were elucidated by spectroscopic data such as 1H &13C NMR and HRMS. The anti-proliferative activity of newly synthesized compounds were assessed in vitro against a panel of four human cancer cell lines, namely IMR-32 (neuroblastoma), DU-145 (prostate), MIAPACA (pancreatic), MCF-7 (breast) along with a normal cell line HEK-293T (embryonic kidney) by employing Sulforhodamine B (SRB) assay. The biological results revealed that majority of synthesized compounds exhibited anti-proliferative activity. In particular, compound 12 was found to be the most potent one as it exhibited five fold higher activity (IC50: 7.9 ± 0.07 µM) than parent compound 1 (IC50: 40.63 ± 0.11 µM) against MCF-7 breast cancer cell line. Flow cytometric analysis of compound 12 revealed that it induced apoptosis and arrested cell cycle in G2/M phase. Mechanistic studies have shown the compound as a potent activator of pro-apoptotic proteins, Bax and Cytochrome-c via the upregulation of tumour suppressor proteins, p53 and PTEN. From the docking studies, it can be inferred that Compound 12 acts as a novel and attractive anti-cancer therapeutic inhibiting the CDK1-Cyclin B complex.

Histone deacetylase (Rpd3) regulates Drosophila early brain development via regulation of Tailless.

Tailless is a committed transcriptional repressor and principal regulator of the brain and eye development in Drosophila. Rpd3, the histone deacetylase, is an established repressor that interacts with co-repressors like Sin3a, Prospero, Brakeless and Atrophin. This study aims at deciphering the role of Rpd3 in embryonic segmentation and larval brain development in Drosophila. It delineates the mechanism of Tailless regulation by Rpd3, along with its interacting partners. There was a significant reduction in Tailless in Rpd3 heteroallelic mutant embryos, substantiating that Rpd3 is indispensable for the normal Tailless expression. The expression of the primary readout, Tailless was correlative to the expression of the neural cell adhesion molecule homologue, Fascilin2 (Fas2). Rpd3 also aids in the proper development of the mushroom body. Both Tailless and Fas2 expression are reported to be antagonistic to the epidermal growth factor receptor (EGFR) expression. The decrease in Tailless and Fas2 expression highlights that EGFR is upregulated in the larval mutants, hindering brain development. This study outlines the axis comprising Rpd3, dEGFR, Tailless and Fas2, which interact to fine-tune the early segmentation and larval brain development. Therefore, Rpd3 along with Tailless has immense significance in early embryogenesis and development of the larval brain.

Imine stilbene analog ameliorate isoproterenol-induced cardiac hypertrophy and hydrogen peroxide-induced apoptosis.

Cardiac hypertrophy is an adaptive response to stress, in order to maintain proper cardiac function. However, sustained stress leads to pathological hypertrophy accompanied by maladaptive responses and ultimately heart failure. At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in myocyte size, reactivation of the fetal gene markers, disassembly of the sarcomere and transcriptional remodelling which are regulated by heart-specific transcription factors like MEF2, GATA4 and immediate early genes like c-jun and c-fos.2. It has been explored and established that the hypertrophic process is associated by oxidative stress and mediated by pathways involving several terminal stress kinases like P38, JNK and ERK1/2. Stilbenoids are bioactive polyphenols and earlier studies have shown that imine stilbene exert cardioprotective and anti aging effects by acting as modulators of Sirt1. The present study was aimed at designing and synthesizing a series of imine stilbene analogs and investigate its anti hypertrophic effects and regulatory mechanism in cardiac hypertrophy and apoptosis. Interestingly one of the analog, compound 3e (10 µM) alleviated isoproterenol (ISO, 25 µM) induced hypertrophy in rat cardiomyocyte (H9c2) cells by showing a marked decrease in the myocyte size. Further, compound 3e also restored the cardiac function by activating the metabolic stress sensor, AMPK. Moreover, molecular docking studies showed stable binding between compound 3e and GSK3ß suggesting that compound 3e may directly regulate GSK3ß activity and ameliorate ISO-induced cardiac hypertrophy. In agreement with this, compound 3e also modulated the crosstalk of all the hypertrophy inducing terminal Kinases by bringing down the expression to near control conditions. The compound also relieved H2O2 (100 µM) mediated ROS and normalized abnormal mitochondrial oxygen demand in hypertrophic conditions indicating the possibility of the compound to show promise in playing a role in cardiac hypertrophy.

Glucose starvation-induced oxidative stress causes mitochondrial dysfunction and apoptosis via Prohibitin 1 upregulation in human breast cancer cells.

In recent years there has been an upsurge in research focusing on reprogramming cancer cells through understanding of their metabolic signatures. Alterations in mitochondrial bioenergetics and impaired mitochondrial function may serve as effective targeting strategies especially in triple-negative breast cancers (TNBCs) where hormone receptors and endocrine therapy are absent. Glucose starvation (GS) of MDA-MB-231 and MCF-7 breast cancer cells showed decrease in mitochondrial Oxygen Consumption Rate (OCR), which was rescuable to control level through addition of exogenous antioxidant N-Acetyl Cysteine (NAC). Mechanistically, GS led to increase in mitochondrial ROS and upregulation of the pleiotropic protein, Prohibitin 1 (PHB1), leading to its dissociation from Dynamin-related protein 1 (DRP1), perturbance of mitochondrial membrane potential (MMP) and triggering of the apoptosis cascade. PHB1 also reduced the invasive and migratory potential of both cell lines. We emphasize that glucose starvation remarkably sensitized the highly glycolytic metastatic TNBC cell line, MDA-MB-231 to apoptosis and decreased its migratory potential. Based on our findings, additional TNBC cell lines can be evaluated and a nutritional paradigm be proposed for anticancer therapy.

Erratum: miR-15a/miR-16 down-regulates BMI1, impacting Ub-H2A mediated DNA repair and breast cancer cell sensitivity to doxorubicin.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Scriptaid cause histone deacetylase inhibition and cell cycle arrest in HeLa cancer cells: A study on structural and functional aspects.

Scriptaid (SCR), a well-known histone deacetylase inhibitor, cause various cellular effects such as cell growth inhibition and apoptosis. In this study, we have evaluated the anti-cancer effects of Scriptaid in HeLa cells, IMR-32 and HepG2 cells. Scriptaid inhibited the growth of HeLa cells with IC50 of 2µM at 48h in a dose-dependent manner. Flow-cytometric analysis indicated that SCR induced apoptosis. Scriptaid was found to inhibit HDAC-8 effectively than other HDAC inhibitor such as TSA as observed by HDAC-8 assay, Western blotting and modelling study. This observation was further strengthened by an artificial neuronal network (ANN) model.

miR-15a/miR-16 down-regulates BMI1, impacting Ub-H2A mediated DNA repair and breast cancer cell sensitivity to doxorubicin.

The B-lymphoma Moloney murine leukemia virus insertion region-1 protein (BMI1) acts as an oncogene in various cancers, including breast cancer. Recent evidence suggests that BMI1 is rapidly recruited to sites of DNA double strand breaks where it facilitates histone H2A ubiquitination and DNA double strand break repair by homologous recombination. Here we show that miR-15a and miR-16 expression is decreased during the initial period after DNA damage where it would otherwise down-regulate BMI1, impairing DNA repair. Elevated miR-15a and miR-16 levels down-regulated BMI1 and other polycomb group proteins like RING1A, RING1B, EZH2 and also altered the expression of proteins associated with the BMI1 dependent ubiquitination pathway. Antagonizing the expression of miR-15a and miR-16, enhanced BMI1 protein levels and increased DNA repair. Further, overexpression of miR-15a and miR-16 sensitized breast cancer cells to DNA damage induced by the chemotherapeutic drug doxorubicin. Our results suggest that miR-15a and miR-16 mediate the down-regulation of BMI1, which impedes DNA repair while elevated levels can sensitize breast cancer cells to doxorubicin leading to apoptotic cell death. This data identifies a new target for manipulating DNA damage response that could impact the development of improved therapeutics for breast cancer.

Novel Triazole linked 2-phenyl benzoxazole derivatives induce apoptosis by inhibiting miR-2, miR-13 and miR-14 function in Drosophila melanogaster.

Apoptosis is an important phenomenon in multi cellular organisms for maintaining tissue homeostasis and embryonic development. Defect in apoptosis leads to a number of disorders like- autoimmune disorder, immunodeficiency and cancer. 21-22 nucleotides containing micro RNAs (miRNAs/miRs) function as a crucial regulator of apoptosis alike other cellular pathways. Recently, small molecules have been identified as a potent inducer of apoptosis. In this study, we have identified novel Triazole linked 2-phenyl benzoxazole derivatives (13j and 13h) as a negative regulator of apoptosis inhibiting micro RNAs (miR-2, miR-13 and miR-14) in a well established in vivo model Drosophila melanogaster where the process of apoptosis is very similar to human apoptosis. These compounds inhibit miR-2, miR-13 and miR-14 activity at their target sites, which induce an increased caspase activity, and in turn influence the caspase dependent apoptotic pathway. These two compounds also increase the mitochondrial reactive oxygen species (ROS) level to trigger apoptotic cell death.

Down-regulation of BORIS/CTCFL efficiently regulates cancer stemness and metastasis in MYCN amplified neuroblastoma cell line by modulating Wnt/ß-catenin signaling pathway.

BORIS/CTCFL is a vital nucleotide binding protein expressed during embryogenesis and gametogenesis. BORIS/CTCFL is the paralogue of transcriptional repressor protein CTCF, which is aberrantly expressed in various malignancies and primarily re-expressed in cancer stem cells (CSCs). The mechanism behind regulation of BORIS in various cancer conditions and tumor metastases is so far not explored in detail. The aim of the study was to understand the influence of BORIS/CTCFL on stemness and metastasis by regulating well-known oncogenes and related signaling pathways. In our study, we have identified a cross-talk between expression of BORIS/CTCFL and Wnt/ß-catenin signaling pathway, which plays a crucial role in various processes including ontogenesis, embryogenesis and maintenance of stem cell properties. Upon knockdown of BORIS/CTCFL, we observed an upregulation of Mesenchymal to Epithelial transition markers such as E-cad and downregulation of Epithelial to Mesenchymal transition markers such as N-CAD, Vimentin, SNAIL, etc. This transition was accomplished by activation of Wnt/ß-catenin signaling pathway by regulating upstream and downstream Wnt associated proteins including ß-catenin, Wnt3a/5a, CD44, MYC etc. We also identified that BMI1, an oncogene belonging to polycomb group expressed positively with levels of BORIS/CTCFL. Our study implicates the role of BORIS/CTCFL in maintenance of stemness and in transition from mesenchymal to epithelial state in MYC amplified neuroblastoma IMR-32 cells. Effectively controlling BORIS/CTCFL levels can inhibit disease establishment and hence can be considered as a potent target for cancer therapy.

PHB in Cardiovascular and Other Diseases: Present Knowledge and Implications.

BACKGROUND: Prohibitin (PHB) is overtly conserved evolutionarily and ubiquitously expressed protein with pleiotropic functions in diverse cellular compartments. However, regulation and function of these proteins in different cells, tissues and in various diseases is different as evidenced by expression of these proteins which is found to be reduced in heart diseases, kidney diseases, lung disease, Crohn's disease and ulcerative colitis but this protein is highly expressed in diverse cancers. The mechanism by which this protein acts at the molecular level in different subcellular localizations or in different cells or tissues in different conditions (diseases or normal) has remained poorly understood. There are several studies reported to understand and decipher PHB's role in diseases and/or cancers of ovary, lung, stomach, thyroid, liver, blood, prostrate, gastric, esophagus, glioma, breast, bladder etc. where PHB is shown to act through mechanisms by acting as oncogene, tumor suppressor, antioxidant, antiapoptotic, in angiogenesis, autophagy etc. OBJECTIVE: This review specifically gives attention to the functional role and regulatory mechanism of PHB proteins in cardiovascular health and diseases and its associated implications. Various molecular pathways involved in PHB function and its regulation are analyzed. CONCLUSION: PHB is rapidly emerging as a critical target molecule for cardiovascular signaling. Progress in delineating CVD and mechanisms of PHB in diverse molecular pathways is essential for determining when and how PHB targeted therapy might be feasible. In this regard, new therapies targeting PHB may best be applied in the future together with molecular profiling of CVD for clinical stratification of disease diagnosis and prognosis.

Prohibitin confers cytoprotection against ISO-induced hypertrophy in H9c2 cells via attenuation of oxidative stress and modulation of Akt/Gsk-3ß signaling.

Numerous hypertrophic stimuli, including ß-adrenergic agonists such as isoproterenol (ISO), result in generation of reactive oxygen species (ROS) and alteration in the mitochondrial membrane potential (Δψ) leading to oxidative stress. This process is well associated with phosphorylation of thymoma viral proto-oncogene Akt (Ser473) and glycogen synthase kinase-3ß (Gsk-3ß) (Ser9), with resultant inactivation of Gsk-3ß. In the present study, we found that the protective defensive role of prohibitin (PHB) against ISO-induced hypertrophic response in rat H9c2 cells is via attenuation of oxidative stress-dependent signaling pathways. The intracellular levels of mitochondrial membrane potential along with cellular ROS levels and mitochondrial superoxide generation were determined. In order to understand the regulation of Akt/Gsk-3ß signaling pathway, we carried out immmunoblotting for key proteins of the pathway such as PTEN, PI3K, phosphorylated, and unphosphorylated forms of Akt, Gsk-3ß, and immunofluorescence experiments of p-Gsk-3ß. Enforced expression of PHB in ISO-treated H9c2 cells suppressed cellular ROS production with mitochondrial superoxide generation and enhanced the mitochondrial membrane potential resulting in suppression of oxidative stress which likely offered potent cellular protection, led to the availability of more healthy cells, and also, significant constitutive activation of Gsk-3ß via inactivation of Akt was observed. Knockdown of PHB expression using PHB siRNA in control H9c2 cells reversed these effects. Overall, our results demonstrate that PHB confers cytoprotection against oxidative stress in ISO-induced hypertrophy and this process is associated with modulation of Akt/Gsk-3ß signaling mechanisms as evident from our PHB overexpression and knockdown experiments.

Simultaneous delivery of Paclitaxel and Bcl-2 siRNA via pH-Sensitive liposomal nanocarrier for the synergistic treatment of melanoma.

pH-sensitive drug carriers that are sensitive to the acidic (pH = ~6.5) microenvironments of tumor tissues have been primarily used as effective drug/gene/siRNA/microRNA carriers for releasing their payloads to tumor cells/tissues. Resistance to various drugs has become a big hurdle in systemic chemotherapy in cancer. Therefore delivery of chemotherapeutic agents and siRNA's targeting anti apoptotic genes possess advantages to overcome the efflux pump mediated and anti apoptosis-related drug resistance. Here, we report the development of nanocarrier system prepared from kojic acid backbone-based cationic amphiphile containing endosomal pH-sensitive imidazole ring. This pH-sensitive liposomal nanocarrier effectively delivers anti-cancer drug (Paclitaxel; PTX) and siRNA (Bcl-2), and significantly inhibits cell proliferation and reduces tumor growth. Tumor inhibition response attributes to the synergistic effect of PTX potency and MDR reversing ability of Bcl-2 siRNA in the tumor supporting that kojic acid based liposomal pH-sensitive nanocarrier as efficient vehicle for systemic co-delivery of drugs and siRNA.