Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor-killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation.

In the past years, PDE5 has emerged as a promising therapeutic target for many cancers due to its highly upregulated expression. Interestingly, a recent in vitro study by our group has shown the antitumor and chemopotentiating action of sildenafil against T cell lymphoma. Our study showed that lower doses of sildenafil (50 µM) and cisplatin (0.5 µg/mL) exhibited 4% and 23% cytotoxicity against HuT78 cells, respectively, which was dramatically increased up to 50% when treated with both. Hence, the present study was designed to evaluate the antitumor and chemo-potentiating action of sildenafil in a murine model of T cell lymphoma (popularly called as Dalton's lymphoma [DL]). In the present study, DL-bearing mice were administered with vehicle (PBS), sildenafil (5 mg/kg bw), cisplatin (5 mg/kg bw), and sildenafil and cisplatin followed by evaluation of their impact on tumor growth by analyzing various parameters. The apoptosis was assessed by Wright-Giemsa, annexin-V, and DAPI staining. Reactive oxygen species (ROS) level was examined through DCFDA staining. The expression of genes and proteins were estimated by RT-PCR and Western blotting, respectively. The experimental findings of the study demonstrate for the first time that sildenafil inhibits tumor growth and potentiates tumor inhibitory ability of cisplatin by altering apoptosis, glycolysis, ROS homeostasis, and pH regulation in T cell lymphoma-carrying host. In addition, our investigation also showed amelioration of tumor-induced liver and kidney damage by sildenafil. Overall, the experimental data of our study strongly advocate the use and repurposing of SDF in designing promising chemotherapeutic regimens against malignancies of T cells.

The antagonist of ß-adrenergic receptor propranolol inhibits T cell lymphoma growth and enhances antitumor efficacy of cisplatin in vivo: A role of modulated apoptosis, glucose metabolism, pH regulation, and antitumor immune response.

Accumulating evidence has shown a vital role of stress-regulatory hormones, including epinephrine, in the progression of numerous cancers, including T cell lymphoma. Further, the antitumor and chemosensitizing potential of propranolol, an inexpensive ß-adrenergic receptor antagonist has also been reported against breast, colon, ovarian, and pancreatic cancers. However, in vivo antitumor and chemopotentiating activity of propranolol have not yet been examined against malignancies of hematological origin, including T cell lymphoma. Therefore, the present study is designed to evaluate the antitumor and chemopotentiating action of propranolol in a T cell lymphoma murine model. In this study, T cell lymphoma-bearing mice were treated with vehicle alone (PBS) or containing propranolol followed by administration of with or without cisplatin. The progression of the tumor was assessed along with analysis of tumor cell apoptosis, glucose metabolism, pH regulation, and antitumor immune response. The apoptosis was estimated by cellular and nuclear morphology analysis through Wright-Giemsa, annexin-V, and DAPI staining. ELISA was used to detect the epinephrine level in serum. The glucose, lactate, and NO levels were measured in the tumor ascitic fluid by calorimetric methods. RT-PCR and Western blot were used to assess the levels of various crucial regulators at gene and protein levels, respectively. Our results showed that propranolol exerts antitumor as well as chemopotentiating ability in DL-bearing mice by altering apoptosis, glycolysis, acidification of TME, and immunosuppression.

Dual targeting pH responsive chitosan nanoparticles for enhanced active cellular internalization of gemcitabine in non-small cell lung cancer.

Lung cancer (LC), related with the enhanced expression of epidermal growth factor receptor (EGFR) and sialic acid binding receptors (glycan) brought about the development of EGFR and glycan receptor specific anticancer therapeutics. The current study assessed the formulation, physiochemical characterization, in vitro and in vivo effects of sialic acid (SA) and cetuximab (Cxmab) decorated chitosan nanoparticles (CSN-NPs) loaded with gemcitabine (GMC) targeted to glycan and EGFR over-expressing non-small-cell lung-cancer (NSCLC) A-549 cells. Chitosan (CSN) was conjugated with sialic acid via EDC/NHS chemistry followed by gemcitabine loaded sialic acid conjugated chitosan nanoparticles (GMC-CSN-SA-NPs) were prepared by ionic gelation method decorated with Cxmab by electrostatic interaction. In vitro cytotoxicity of NPs quantified using cell based MTT, DAPI and Annexing-V/PI apoptosis assays showed superior antiproliferative activity of targeted nanoformulations (GMC-CSN-SA-Cxmab-NPs â‰« GMC-CSN-SA-NPs, GMC-CSN-Cxmab-NPs) over non-targeted nanoformulation (GMC-CSN-NPs) against A-549 cells. In vivopharmacokinetic study showed superior bioavailability and in vivo therapeutic efficacy investigation exhibited strongest anticancer activity of glycan and EGFR targeted NPs (GMC-CSN-SA-Cxmab-NPs). GMC-CSN-SA-Cxmab-NPs demonstrated enhanced cellular internalization and better therapeutic potential, by specifically targeting glycan and EGFR on NSCLC A-549 cells and B[a]P induced lung cancer mice model, hence it might be a good substitute for non-targeted, conventional chemotherapy.

Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism.

In recent years, studies have reported the role of stress-regulatory hormones, including epinephrine, in regulating the progression of a few cancers. However, the tumor-promoting action of epinephrine is not yet investigated in T cell malignancy, a rare and complicated neoplastic disorder. More so, very little is known regarding the implication of epinephrine in the glucose metabolic rewiring in tumor cells. The present investigation showed that epinephrine enhanced the proliferation of T lymphoma cells through up- and down-regulating the expression of PCNA, cyclin D, and p53, respectively. In addition, epinephrine inhibited apoptosis in T lymphoma cells possibly by increasing the level of BCL2 (an anti-apoptotic protein) and decreasing PARP level (a pro-apoptotic protein). Intriguingly, epinephrine is reported to stimulate glycolysis in T lymphoma cells by increasing the expression of crucial glycolysis regulatory molecules, namely HKII and PKM2, in a HIF-1α-dependent manner. Moreover, augmented production of ROS has been observed in T lymphoma cells, which might be a central player in epinephrine-mediated T cell lymphoma growth. Taken together, our study demonstrates that epinephrine might have a significant role in the progression of T cell lymphoma.

Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism.

Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.

Molecular and cellular paradigms of multidrug resistance in cancer.

BACKGROUND: The acquisition of resistance to chemotherapy is a major hurdle in the successful application of cancer therapy. Several anticancer approaches, including chemotherapies, radiotherapy, surgery and targeted therapies are being employed for the treatment of cancer. However, cancer cells reprogram themselves in multiple ways to evade the effect of these therapies, and over a period of time, the drug becomes inactive due to the development of multi-drug resistance (MDR). MDR is a complex phenomenon where malignant cells become insensitive to anticancer drugs and attain the ability to survive even after several exposures of anticancer drugs. In this review, we have discussed the molecular and cellular paradigms of multidrug resistance in cancer. RECENT FINDINGS: An Extensive research in cancer biology revealed that drug resistance in cancer is the result of perpetuated intracellular and extracellular mechanisms such as drug efflux, drug inactivation, drug target alteration, oncogenic mutations, altered DNA damage repair mechanism, inhibition of programmed cell death signaling, metabolic reprogramming, epithelial mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic changes, redox imbalance, or any combination of these mechanisms. An inevitable cross-link between inflammation and drug resistance has been discussed. This review provided insight molecular mechanism to understand the vulnerabilities of cancer cells to develop drug resistance. CONCLUSION: MDR is an outcome of interplays between multiple intricate pathways responsible for the inactivation of drug and development of resistance. MDR is a major obstacle in regimens of successful application of anti-cancer therapy. An improved understanding of the molecular mechanism of multi drug resistance and cellular reprogramming can provide a promising opportunity to combat drug resistance in cancer and intensify anti-cancer therapy for the upcoming future.

Nimbolide induces cell death in T lymphoma cells: Implication of altered apoptosis and glucose metabolism.

Nimbolide is a tetranortriterpenoid derived from the leaves and flowers of Azadirachta indica (Neem). It exhibits anticancer activity against a variety of cancers by modulating various crucial features, including cell proliferation, apoptosis, and invasion and metastasis. More importantly, the cytotoxic effect of nimbolide has also been observed against T cell lymphoma, but the underlying mechanisms are still unexplored. So far, no study has been conducted to observe the effect of nimbolide on cancer cell metabolism. Therefore, the present investigation was designed to explore the molecular mechanisms of the antitumor potential of nimbolide against T cell lymphoma, a neoplastic disorder of thymic origin. In addition, we also unraveled the anti-glycolytic activity of nimbolide against T lymphoma cells with possible molecular mechanisms. Our results showed the cytotoxic action of nimbolide against three different cell lines of T cell lymphoma, namely Dalton's lymphoma, HuT-78, and J6. Nimbolide-induced apoptosis in T lymphoma cells by altering the level of reactive oxygen species, p53, Bcl2, Bax, and cytochrome c, with subsequent cleavage of caspase 3. Remarkably, nimbolide inhibited the expression of hypoxia-inducible factor-1α, glucose transporter 3, hexokinase II, and pyruvate dehydrogenase kinase 1, which led to the suppression of glycolysis with concomitant activation of oxidative phosphorylation. Hence, the results of the present investigation demonstrate that nimbolide exerts tumoricidal activity against T lymphoma cells via augmentation of apoptosis and reversal of altered cell metabolism. Thus, the present study provides a new insight for the therapeutic utilization of nimbolide against T cell lymphoma.

Lysophosphatidic acid promotes survival of T lymphoma cells by altering apoptosis and glucose metabolism.

Lysophosphatidic acid (LPA) is a bioactive lipid, which plays an indispensable role in various physiological and pathological processes. Moreover, an elevated level of LPA has been observed in malignancies of different origins and implicated in their progression via modulation of proliferation, apoptosis, invasion and metastasis. Interestingly, few recent reports suggest a pivotal role of LPA-modulated metabolism in oncogenesis of ovarian cancer. However, little is understood regarding the role of LPA in the development and progression of T cell malignancies, which are considered as one of the most challenging neoplasms for clinical management. Additionally, mechanisms underlying the LPA-dependent modulation of glucose metabolism in T cell lymphoma are also not known. Therefore, the present study was undertaken to explore the role of LPA-altered apoptosis and glucose metabolism on the survival of T lymphoma cells. Observations of this investigation suggest that LPA supports survival of T lymphoma cells via altering apoptosis and glucose metabolism through changing the level of reactive species, namely nitric oxide and reactive oxygen species along with expression of various survival and glucose metabolism regulatory molecules, including hypoxia-inducible factor 1-alpha, p53, Bcl2, and glucose transporter 3, hexokinase II, pyruvate kinase muscle isozyme 2, monocarboxylate transporter 1, pyruvate dehydrogenase kinase 1. Taken together' the results of the present investigation decipher the novel mechanisms of LPA-mediated survival of T lymphoma cells via modulation of apoptosis and glucose metabolism.