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Sacituzumab govitecan is an antibody-drug conjugate. It is composed of a humanized monoclonal antibody raised against the trophoblast cell-surface antigen 2 (Trop-2), and linked to SN-38, which is an active metabolite of topoisomerase I inhibitor anticancer drug irinotecan. A hydrolyzable linker conjugates the antibody and the drug. Trop-2 is overexpressed in various tumors including the triple-negative breast cancers (TNBCs) that are more aggressive with limited therapeutic options. Sacituzumab govitecan has proven to be an important therapeutic modality to manage the TNBCs. It has shown progression-free survival (PFS) and overall survival (OS) benefits when compared to standard-of-care chemotherapeutics. Accordingly, it is approved for the treatment of TNBCs in the United States and the European Union. Sacituzumab govitecan has also shown PFS and OS benefits for hormone receptor-positive (HR+) and human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancers. Therefore, sacituzumab govitecan appears to be an option for HR+/HER2- metastatic breast cancers that are heavily pretreated and exhibit endocrine resistance. Although sacituzumab govitecan has shown promise, it also is toxic. Additional studies are therefore needed to further refine the use of sacituzumab govitecan in improving the management of metastatic breast cancer., Competing Interests: Conflicts of Interest The authors have no relevant conflicts of interest to declare.

The cyclin-dependent kinase (CDK) inhibitors have emerged as important cancer therapeutics. To date, three CDK4/6 inhibitors in combination with endocrine therapy have been approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. These include, palbociclib, ribociclib and abemaciclib. More recently, a newer CDK4/6 inhibitor named dalpiciclib has been tested in the phase III DAWNA-1 study, which is a randomized, double-blind, placebo-controlled trial that investigates dalpiciclib in combination with fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer patients that have relapsed or progressed on prior endocrine therapy. Dalpiciclib is an oral agent and an emerging ATP-competitive CDK4/6 inhibitor. The interim results of DAWNA-1 study revealed that dalpiciclib in combination with fulvestrant significantly prolonged the progression-free survival. The clinical use and side effects of palbociclib, ribociclib and abemaciclib as well as dalpiciclib are reviewed here., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to declare.

Genotoxic chemotherapeutics particularly cisplatin remain effective for clinical management of various malignancies including lung cancer. However, the development of chemoresistance leads to treatment failure. The mechanisms by which tumor cells acquire resistance to chemotherapy are multifaceted in nature and some remain to be fully elucidated. Recently, a potential role of RNA-binding protein hnRNPA0 in chemoresistance of p53-defective lung cancer cells was reported. Genotoxic (DNA damaging) chemotherapy was reported to activate hnRNPA0 which in turn post-transcriptionally regulated p27 Kip1 and Gadd45-alpha by stabilizing their mRNAs. Regulation of p27 Kip1 and Gadd45-alpha led to enforcement of G1/S and G2/M checkpoints thereby providing time for DNA repair and thus, resistance to chemotherapy. The identification of a signaling network involving the kinase MK2, hnRNPA0, p27 Kip1 and Gadd45-alpha that may predict response to chemotherapy is an interesting finding. Further studies are now needed to gain additional insights as to whether this network is restricted only to a subset of tumors or more broadly relevant across multiple tumor types.

Malignant melanoma remains one of the fastest growing cancers worldwide. Although the primary cutaneous melanoma can be managed by surgery, the advanced metastatic melanoma cannot be managed by surgery alone and thus, requires better therapeutic approaches. In view of high mortality rates due to metastatic melanoma, better understanding of the molecular pathogenesis of malignant melanoma is urgently needed. Such information is expected to prove very valuable in early detection of potential metastatic lesions and developing newer therapeutic approaches in order to better manage this malignancy. This article reviews the available information on the molecular changes associated with malignant melanoma and discusses the potential of such information in facilitating the development of newer anti-melanoma therapeutics. Current state of knowledge and the future of traditional and newly approved anti-melanoma therapeutics are also discussed.

Mitochondrial morphology and metabolism play an important role in cellular homeostasis. Recent studies have shown that the fidelity of mitochondrial morphology is important in maintaining mitochondrial shape, number, size, membrane potential, ATP synthesis, mtDNA, motility, signaling, quality control, response to cellular stress, mitophagy and apoptosis. This article provides an overview of the current state of knowledge of the fission and fusion machinery with a focus on the mechanisms underlying the regulation of the mitochondrial morphology and cellular energy state. Several lines of evidence indicate that dysregulation of mitochondrial fission or fusion is associated with mitochondrial dysfunction, which in turn impacts mitophagy and apoptosis. Metabolic disorders are also associated with dysregulation of fission or fusion and the available lines of evidence point to a bidirectional interplay between the mitochondrial fission or fusion reactions and bioenergetics. Clearly, more in-depth studies are needed to fully elucidate the mechanisms that control mitochondrial fission and fusion. It is envisioned that the outcome of such studies will improve the understanding of the molecular basis of related metabolic disorders and also facilitate the development of better therapeutics.

Cellular response to DNA damage is multifacted in nature and involves a complex signaling network in which p53 functions as a "molecular node" for converging signals. p53 has been implicated in a variety of cellular processes primarily functioning as a transcription factor and also in a transcription-independent manner. It is rapidly activated following DNA damage with phosphorylation as one of the initial signals. Cellular context as well as the type and severity of DNA damage determine p53 activation code, and its activities are regulated predominantly through protein degradation, post-translational modification and interactions with various cellular co-factors. These events are crucial in decision making by p53 as it has the ability to receive, assess and integrate different signals and route them accordingly to induce cell death or promote cell survival. In this decision making process, its transcriptional role to activate a specific subset of target genes linked to inducing cell cycle arrest or apoptosis is critical that is further fine-tuned by its transcription-independent function. This article reviews the current state of knowledge about the role of p53 in determining the fate of cells that have incurred DNA damage.

Homeodomain-interacting protein kinases including HIPK1, HIPK2 and HIPK3 are serine/threonine kinases that form a family of highly conserved kinases. HIPKs are involved in diverse cellular functions including regulation cell death, survival, proliferation and differentiation. Here we report the characterization of a human HIPK4 that we identified in a proteomic screen during our efforts to unravel novel markers linked to cell death and survival. Human HIPK4 protein is composed of 616 residues with predicted molecular mass of 69.425 kDa and harbors a serine/threonine protein kinase catalytic domain at its N-terminal end. In the in vitro kinase assay, HIPK4 exhibits kinase activity and mutation of the conserved lysine 40 or aspartic acid 136 residue in its catalytic domain inactivates its kinase function. Human HIPK4 harbors multiple putative serine/threonine- and tyrosine-specific phsophorylation sites and also contains four high probability sumoylation sites, findings that suggest its function to be modulated by post-translational modifications. HIPK4 has been so named in the database because of its sequence homology to HIPK1, 2 and 3 predominantly within its catalytic domain. However, HIPK4 is smaller in size than the known HIPKs and has additional distinct features suggesting it to be a unique member of the HIPK family. Further functional characterization of HIPK4 is needed and will prove valuable to ascertain whether it performs distinct functions or share overlapping functions with other HIPKs.

Pirh2 is an E3 ubiquitin ligase that promotes tumor suppressor p53 ubiquitination and proteasomal degradation. Recently, we have reported the identification and characterization of two novel isoforms of Pirh2 named Pirh2B and Pirh2C and accordingly, reclassified the full-length Pirh2 as Pirh2A. Both Pirh2B and C negatively regulate p53 and also exhibit interactions with MDM2. Here, we report the existence of an additional Pirh2 isoform that we have named Pirh2D. Translation of nucleotide sequence predicts Pirh2D to be composed of 75 amino acids with a molecular mass of 8493.74 Da. Thus, Pirh2D is a truncated protein that harbors 67 amino-terminal amino acids identical to those in Pirh2A, Pirh2B and Pirh2C and has 8 additional unique amino acids at the carboxyl-terminal end. Further studies are needed to determine whether Pirh2D also functions in a manner similar to Pirh2B and Pirh2C.

Sulindac, the non-steroidal anti-inflammatory drug has shown promise in the prevention of colon cancer but the molecular mechanisms by which it mediates such effects remain to be elucidated. Sulindac sulfide is the major active metabolite of sulindac and believed to be responsible for mediating the effects of sulindac. Previously, our group and others have shown that sulindac sulfide induces apoptosis by engaging death receptor and mitochondrial pathways and that a cross-talk exists between these two pathways during sulindac sulfide-induced apoptosis. Second mitochondrial-derived activator (Smac) is an important pro-apoptotic molecule that activates caspases by antagonizing the inhibitors of apoptosis (IAPs). In this study, we have utilized Smac-proficient and -deficient human colon cancer cells to investigate the role of Smac during sulindac sulfide-induced apoptosis and found that Smac deficiency affects sulindac sulfide-induced apoptosis in human colon cancer cells. Sulindac sulfide-induced apoptosis is coupled with upregulation of death receptor 5 (DR5), and activation of caspases 3, 9 and 8 in Smac-proficient cells. In Smac-deficient cells, although sulindac sulfide-induced DR5 upregulation is not altered, activation of caspases 3, 9 and 8 is affected. Smac deficiency also abrogates sulindac sulfide-induced cytochrome c release from mitochondria into cytosol. Our results, therefore, demonstrate that Smac is involved in sulindac sulfide-induced apoptotic signal transduction in human colon cancer cells and highlight the existence of a potential cross-talk between Smac and cytochrome c.

Thapsigargin (TG) is a sesquiterpen lactone that inhibits the endoplasmic reticulum (ER) calcium ATPases to disrupt calcium homeostasis and consequently induces ER stress. We have previously reported that TG induces apoptosis by engaging the death receptor 5 (DR5) and the intrinsic pathways. Second mitochondrial-derived activator (Smac) is an important modulator of apoptosis that induces activation of caspases by antagonizing inhibitors of apoptosis (IAPs). In this study, we have utilized Smac-proficient and -deficient human colon cancer cells to investigate the effects of Smac deficiency during ER-stress-induced apoptosis. Our results indicate that Smac deficiency considerably affects ER stress-induced apoptosis in human colon cancer cells. For example, ER stress inducing agent TG upregulates DR5, and activates caspases 3, 9 and 8 in Smac-proficient cells. In Smac-deficient cells, although TG-induced DR5 upregulation is not affected, activation of caspases 3, 9 and 8 is affected. Smac deficiency also affects TG-induced cytochrome c release from mitochondria into cytosol suggesting the existence of a potential cross-talk between Smac and cytochrome c. Thus, our results indicate that ER stress-induced apoptosis also engages Smac for transduction of apoptotic signals in human colon cancer cells and that a potential feedback signaling between Smac and cytochrome c appears to modulate the intrinsic pathway of apoptosis.