MortaparibPlus- A Novel Anticancer Small Molecule Abrogating Mortalin-p53 Interaction in Cancer Cells

Background. The cessation of tumor cell growth through cell cycle arrest and apoptosis is determined by p53, a tumor suppressor protein. However, the interaction between mortalin-p53 within cytoplasm/nucleus leads to the inactivation of p53 transcriptional activation function. The disruption of mortalin-p53 complex has been suggested as an approach for developing a potential anticancer drug. Methods. A screening of a high-content chemical library was performed to determine a molecule with mortalin-p53-interaction disrupting characteristics. After four-rounds of visual assays, we discovered a triazole derivative (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole, named MortaparibPlus) with a potential ability of disrupting mortalin-p53-complex. In this study, we recruited two types of cells (different p53 status and point mutation), Colorectal Cancer Cells [HCT116 (p53WT) and DLD-1 (p53 (p53S241F)] and Luminal A Breast Cancer [MCF-7 (p53WT) and T47D (p53L194F)]. We further validated the activity of MortaparibPlus by bioinformatics/experimental analyses. Results. Through bioinformatics analysis, we discovered that MortaparibPlus has potential to block the binding site of mortalin on p53, thus, preventing the formation of mortalin-p53 complex. Immunoprecipitation analyses showed that MortaparibPlus abrogated the mortalin-p53 complex formation and caused growth arrest/apoptosis (via activation of p21WAF1, BAX, and PUMA) in HCT116, DLD-1, and MCF-7 cells. Furthermore, MortaparibPlus posed a cytotoxic effect to cancer cells through various mechanisms (inhibition of PARP1, up-regulation of p73 proteins, downregulation of mortalin and CARF proteins). In contrast, we found that, despite the hyperactivation of PARP1 (PAR accumulation and loss of ATP) as an alternative tumor suppression mechanism, MortaparibPlus-treated T47D cells exhibited signs of neither complete apoptosis nor PAR-Thanatos. Such response was associated with the failure of MortaparibPlus to inhibit the formation of AIF-mortalin complexes. Conclusions. MortaparibPlus is proposed as a potential multimodal small molecule for cancer treatment that requires further extensive laboratory and clinical studies

A monoclonal antibody against annexin A2 targets stem and progenitor cell fractions in tumors.

The involvement of cancer stem cells (CSCs) in driving tumor dormancy and drug resistance is well established. Most therapeutic regimens however are ineffective in targeting these regenerative populations. We report the development and evaluation of a monoclonal antibody, mAb150, which targets the metastasis associated antigen, Annexin A2 (AnxA2) through recognition of a N-terminal epitope. Treatment with mAb150 potentiated re-entry of CSCs into the cell cycle that perturbed tumor dormancy and facilitated targeting of CSCs as was validated by in vitro and in vivo assays. Epigenetic potentiation further improved mAb150 efficacy in achieving total tumor regression by targeting regenerative populations to achieve tumor regression, specifically in high-grade serous ovarian adenocarcinoma

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that cause millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients’ disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient’s physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.All the authors are highly grateful and acknowledge to the authority of the respective departments and institutions for their support in carrying out this research. The authors also express their sincere gratitude to the unknown referee for critically reviewing the manuscript and suggesting useful changes. This research was funded by "Agencia Canaria de Investigación, Innovación y Sociedad de la Información (ACIISI) del Gobierno de Canarias” (No. ProID2020010134), and o´Caja Canarias (Project No. 2019SP43).Peer reviewe