Lung cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains a major obstacle to the effectiveness of long-term treatment, eventually leading to therapeutic insensitivity, poor progression-free survival, and disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations in the tumor microenvironment, and several other cellular and molecular alterations. A better understanding of these mechanisms is crucial for targeting factors involved in therapeutic resistance, establishing novel antitumor targets, and developing therapeutic strategies to resensitize cancer cells towards treatment. In this review, we summarize diverse mechanisms driving resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and promising strategies to help overcome this therapeutic resistance.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood–brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.
Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer’s disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-β-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.
Lung cancer is the leading cause of cancer-related death in the United States, with a 5-year survival rate of less than 25%. While most lung cancer patients receive radiation therapy, radioresistance severely impacts treatment outcomes. Thus, development of therapeutics to potentiate durable response to radiation therapy may be key to improving treatment outcomes. Research in our lab has previously implicated heme, a central biosynthetic molecule with important functions in diverse molecular and cellular processes, in lung cancer development and progression. To target heme, we designed heme-sequestering protein 2 (HeSP2) which displays potent anti-tumor activity in mouse tumor models. By decreasing tumor metabolic demand through heme sequestration, HeSP2 can significantly alleviate tumor hypoxia, a dominant radioresistance mechanism. Tumor hypoxia correlates with poor clinical outcomes by acting via multiple mechanisms such as inhibiting radiation-induced DNA damage and inducing the HIF-1 pathway that leads to antioxidant generation. Here, our preliminary data show that HeSP2 potentiates the antitumor efficacy of ionizing radiation. To see the effect of HeSP2 in combination with radiotherapy, in summary we subcutaneously implanted A549-luc, NSCLC cell lines with mutation in Kras and KLB1 in SCID mice. After 1-2 weeks mice were treated with saline (Control), HeSP2(25 mg/kg, i.v, twice a week), radiation (5 Gray, once per week at week 2 and 3), and HeSP2 combined with radiation (25 mg/kg, i.v, twice a week plus 5 Gray, once per week at week 2 and 3. Tumor tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC). Preliminary results indicate HeSP2 in combination with radiation reduce the levels of multiple angiogenic markers and vascular markers as well as microvessel density. These results indicate that heme sequestration in combination with radiation can be an effective strategy for suppressing lung tumors. Citation Format: Narges Salamat, Tianyuan Wang, Eranda Berisha, Maria Del Carmen Chacon Castro, Adnin Ashrafi, Debabrata Saha, Ralph P. Mason, Li Liu, Li Zhang. Evaluation of heme inhibitory therapy in combination with radiation of lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4979.
Breast cancer (BC) is the second leading cause of cancer death in women. Among the four main types of BC, triple-negative breast cancer (TNBC) accounts for 10 to 15% of BC. Although most TNBC patients have a poor prognosis, there are subsets of patients with tumors that respond well to chemotherapy. However, the outcome of chemotherapy in TNBC worsens over time due to the high expression of the oxidative phosphorylation (OXPHOS) complex. Likewise, drug resistant TNBC cells depend on OXPHOS; targeting oxidative metabolism and mitochondrial respiration can potentially overcome their drug resistance. Our lab recently engineered a heme-sequestering protein 2 (HeSP2) based on HasA hemophore. HeSP2 can effectively inhibit heme uptake and decrease the OXPHOS levels in cancer cells due to its high affinity for heme. Another agent, cyclopamine tartrate (CycT), previously known as a modulator of hedgehog signaling and mitochondrial respiration, can inhibit heme synthesis and reduce the OXPHOS levels. Therefore, using these heme-targeting agents in combination with chemotherapy could be an effective strategy to increase the therapeutic efficacy in TNBC. Cisplatin and etoposide are two chemotherapeutic drugs that have recently been used for treating TNBC. For this purpose, we examine the combination therapy of our OXPHOS inhibitory agents, HeSP2 and CycT, with cisplatin and etoposide in TNBC. In vitro experiment using three different TNBC cell lines, 4T1-Fluc-Neo, EMT6_Fluc_Puro, and MDA-MBA-231 confirmed the inhibitory effect of both HeSP2 and CycT in cell proliferation and colony formation in combination with or without chemo drugs. Results indicate that combination therapy significantly reduced the proliferation and inhibited colony formation in TNBC cells. As HeSP2 and CycT are therapeutic agents that reduce hypoxia and OXPHOS, they may also delay the emergence of drug resistance in cancer cells treated with chemotherapy. Our results indicate that HeSP2 and CycT in combination with chemotherapy drugs could serve as a promising therapy to diminish the tumorigenic function in TNBC and overcome resistance to chemotherapy. Citation Format: Parinaz Sadat Alemi, Maria del Carmen Chacon Castro, Eranda Berisha, Zakia Akter, Li Zhang. Combination therapy of heme inhibitory protein (HeSP2) and Cyclopamine tartrate (CycT) with chemotherapeutic drugs is an effective strategy for treatment of TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2681.
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