A Comprehensive Review on Therapeutic Potentials of Natural Cyclic Peptides

Cyclic peptides have emerged as a promising class of organic compounds that possess polypeptide chains with a cyclic ring structure. There is a circular sequence of bonds in which the ring structure is formed via linkage between one end of the peptide bond and the other end with an amide bond or any other chemically stable bonds like ether, thioether, lactone, and disulfide. Generally, the cyclic peptides are isolated from natural resources like invertebrate animals, micro-organisms of marine habitats, and higher plants. These cyclic peptides possess unique structures with diverse pharmacological activities. Now a day, cyclic peptides possess superior therapeutic value due to several reasons such as greater resistance to enzymatic degradation (in vivo) and higher bio-availability. Some of these cyclic peptides are rich in leucine, proline while some have other amino acids as their major constituents. Numerous novel cyclic peptides isolated from natural sources are successfully developed as bioactive products. Recently, cyclic peptides derived from natural resources have attracted attention for exploring their numerous beneficial effects. Moreover, it is reported that natural cyclic peptides exhibit various therapeutic activities like an anthelmintic, ACE inhibitor, anti-tumor, microtubule inhibitor, anti-fungal, anti-malarial, and platelet aggregation inhibiting activity. In this review, various cyclic peptides are reported with structures and biological activities that are isolated from various natural sources. The natural cyclic peptides possess a wide spectrum of biological activities and can become a drug of the future for replacing the existing drugs which develop resistance

Revising the Role of Cortical Cytoskeleton during Secretion: Actin and Myosin XI Function in Vesicle Tethering

In plants, secretion of cell wall components and membrane proteins plays a fundamental role in growth and development as well as survival in diverse environments. Exocytosis, as the last step of the secretory trafficking pathway, is a highly ordered and precisely controlled process involving tethering, docking, and fusion of vesicles at the plasma membrane (PM) for cargo delivery. Although the exocytic process and machinery are well characterized in yeast and animal models, the molecular players and specific molecular events that underpin late stages of exocytosis in plant cells remain largely unknown. Here, by using the delivery of functional, fluorescent-tagged cellulose synthase (CESA) complexes (CSCs) to the PM as a model system for secretion, as well as single-particle tracking in living cells, we describe a quantitative approach for measuring the frequency of vesicle tethering events. Genetic and pharmacological inhibition of cytoskeletal function, reveal that the initial vesicle tethering step of exocytosis is dependent on actin and myosin XI. In contrast, treatments with the microtubule inhibitor, oryzalin, did not significantly affect vesicle tethering or fusion during CSC exocytosis but caused a minor increase in transient or aborted tethering events. With data from this new quantitative approach and improved spatiotemporal resolution of single particle events during secretion, we generate a revised model for the role of the cortical cytoskeleton in CSC trafficking.

Revising the Role of Cortical Cytoskeleton During Secretion: Actin and Myosin XI Function in Vesicle Tethering

In plants, secretion of cell wall components and membrane proteins plays a fundamental role in growth and development as well as survival in diverse environments. Exocytosis, as the last step of the secretory trafficking pathway, is a highly ordered and precisely controlled process involving tethering, docking, and fusion of vesicles at the plasma membrane (PM) for cargo delivery. Although the exocytic process and machinery are well characterized in yeast and animal models, the molecular players and specific molecular events that underpin late stages of exocytosis in plant cells remain largely unknown. Here, by using the delivery of functional, fluorescent-tagged cellulose synthase (CESA) complexes (CSCs) to the PM as a model system for secretion, as well as single-particle tracking in living cells, we describe a quantitative approach for measuring the frequency of vesicle tethering events. Genetic and pharmacological inhibition of cytoskeletal function, reveal that the initial vesicle tethering step of exocytosis is dependent on actin and myosin XI. In contrast, treatments with the microtubule inhibitor, oryzalin, did not significantly affect vesicle tethering or fusion during CSC exocytosis but caused a minor increase of transient or aborted tethering events. With data from this new quantitative approach and improved spatiotemporal resolution of single particle events during secretion, we generate a revised model for the role of the cortical cytoskeleton in CSC trafficking.

Belantamab Mafodotin and Relapsed/Refractory Multiple Myeloma: This Is Not Game Over

Although the therapeutic landscape for multiple myeloma (MM) has expanded, the disease always tends to relapse. In attempt to obtain deep and durable responses, each relapse requires the use of a new strategy. In recent years, new treatment options have emerged even for heavily treated patients. Novel, well-tolerated and highly effective therapies in the relapsed/refractory (RRMM) setting currently represent a real hope. Belantamab mafodotin (BLENREP™) is a first-in-class monoclonal antibody-drug conjugate (ADC) whose target is B-cell maturation antigen (BCMA) conjugated to the cytotoxic microtubule inhibitor monomethyl auristatin F (MMAF). Here, we present two cases of heavily pre-treated RRMM patients that were favorably treated with Belantamab mafodotin, obtaining at least a partial response. Treatment was well tolerated and is ongoing. This is a rare report on real life clinical use of Belantamab mafodotin outside of controlled clinical trials and provide information on efficacy and safety of this anti-myeloma new class of drugs.

Combrestatin derivatives as microtubular assembly inhibitors at colchicine binding site

: Colchicine binding site in microtubules is among the most flourishing target for anticancer remedy. Microtubule inhibitor drugs, including combrestatin phosphate, paclitaxel and Vinca alkaloids, were formerly considered to exert their activity primarily by increasing or decreasing the cellular microtubule mass. This review describes the microtubular assembly along with the combrestatin derivatives as microtubules inhibitors, the structures of compounds known to interact with colchicines binding site, and their possible mechanism of action. Additionally, we have also discussed the utility of other heterocyclic rings and their combrestatin derivatives in treating cancer. Colchicines binding site represents a stimulating new molecular target in the design of combrestatin drugs.

Polatuzumab Vedotin As a Salvage Treatment in Relapsed or Refractory DLBCL: Single Center Experience

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for approximately 25% of all newly diagnosed patients (Swerdlow et. al. IARC, 2017). It is estimated that 40% of patients are refractory to, or relapse after treatment with chemo-immunotherapy (R-CHOP). Salvage therapy with autologous stem-cell transplantation (ASCT) can cure around 40% of those patients, nevertheless, the prognosis is poor for most patients with R/R DLBCL who are relapsed after, or ineligible for ASCT, and in those with suboptimal response to salvage chemotherapy. Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate delivering monomethyl auristatin E (MMAE), a microtubule inhibitor. It was granted accelerated approval by the US FDA on June 2019 for treatment of R/R DLBCL after at least two prior therapies, in combination with bendamustine and rituximab. We herein report our experience on the use of polatuzumab in patients with R/R DLBCL. Methods: Retrospective-single center review on the use of polatuzumab vedotin as part of a compassionate program in patients with R/R DLBCL between June 2018 and July 2021. Inclusion criteria for the study were: age ≥ 18 years, R/R DLBCL [both de-novo and transformed lymphoma], 2 or more prior lines of therapy, and treatment with polatuzumab-based therapy for at least 1 cycle. Patients with CNS involvement were excluded. The compassionate use access program provided polatuzumab at a dose of 1.8 mg/kg, administered with or without bendamustine (up to two doses of 90 mg/m2,) and rituximab (375 mg/m2). Treatment was given every 21 days for up to 6 cycles. Results: we identified 3 patients with R/R DLBCL who were treated with polatuzumab-based therapy. The median number of prior therapies was 2 (2 - 5). The median IPI and CNS-IPI score were 2, (1 - 4) and 2, (2 - 5), respectively (Baseline characteristics are summarized in Table). The median number of Pola-BR cycles received was 3 (2 - 6). One patient completed 6 cycles of polatuzumab with bendamustine and rituximab and achieved partial response. The other two patients were taken of treatment at the time of progression on cycles number 1 and 3. Treatment options were limited after polatuzumab-based therapy. The patient who achieved partial response after 6 cycles of Pola-BR maintained that response for 11 months without additional treatment and died due to COVID-19 associated pneumonia. One patient been screened for Glofitamab compassionate use program, and one patient elected to receive no further therapy. Conclusions: Polatuzumab-based treatment in R/R DLBCL is a promising treatment in an otherwise difficult to treat patient population. The compassionate use program provides access in developing countries to an otherwise prohibitively expensive emerging therapeutic armamentarium in R/R DLBCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Air plasma-activated medium exerts tumor-specific cytotoxicity via the oxidative stress-induced perinuclear mitochondrial clustering

Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy eliminating cancers effectively and safely is the current clinical choice. Since aggressive tumors have inherent or acquired resistance to multidisciplinary therapies targeting apoptosis, tumor-specific induction of another cell death modality is a promising avenue to meet the goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can induce cell death in OS and OC via a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) because of the characteristic unipolar mitochondrial perinuclear aggregation. APAM had potent antitumor activity both in vitro and in vivo. APAM caused apoptosis, necrotic cell death, and autophagy. APAM contained hydrogen peroxide and increased mitochondrial ROS (mROS), while the antioxidant N-acetylcysteine (NAC) prevented cell death. MPMC occurred following mitochondrial fragmentation coinciding with nuclear damages. MPMC was accompanied by the tubulin network remodeling and mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC and the microtubule inhibitor, Nocodazole. Increased Cardiolipin (CL) oxidation was also seen, and NAC and the peroxy radical scavenger Ferrostatin-1 prevented it. In contrast, in fibroblasts, APAM induced minimal cell death, mROS generation, mLPO accumulation, CL oxidation, and MPMC. These results suggest that MPMC is a tumor-specific cause of cell death via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC might serve as a promising target for exerting tumor-specific cytotoxicity.

Paradoxical implication of BAX/BAK in the persistence of tetraploid cells

Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of β-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca2+ stores and store-operated Ca2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca2+ fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.

Application of Box–Behnken Design and Desirability Function in the Development and Optimization of Stealth Liposomes of Microtubule Inhibitor

Aims: The aim of the present study was to develop and optimize a Stealth Liposomal Drug Delivery System of microtubule inhibitor using Box–Behnken Design and Desirability function. Study Design: Development and Optimization of Stealth Liposomes. Place and Duration of Study: The study was carried out in the Department of Pharmacy, Annamalai University, between September 2020 and May 2021. Methodology: Stealth Liposomes were prepared by the thin-film hydration method (TFH). The formulation was optimized using Box – Behnken design to study the effect of independent variables, Amount of Egg Phosphatidylcholine (X1), Amount of Cholesterol (X2), and Amount of DSPE-PEG 2000(X3) on dependent variables Entrapment Efficiency (Y1) and In-vitro drug release (Y2). Results: Entrapment efficiency of the Stealth Liposomes ranges from 56.35 to 84.25%and in-vitro release ranges from 62.38 to 94.26%. The optimized formulation was found using the desirability function to get maximum entrapment with maximum drug release. The optimized formulation showed entrapment efficiency of 80.46% and in-vitro release of 90.11%. Conclusion: Stealth Liposomal Drug Delivery System for microtubule inhibitor was successfully developed and optimized using desirability function in Design Expert software by a three-factor, three level Box – Behnken design.