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Allegra A, Imbesi C, Bitto A, Ettari R. Drug Repositioning for the Treatment of Hematologic Disease: Limits, Challenges and Future Perspectives. Curr Med Chem 2021; 28:2195-2217. [PMID: 33138750 DOI: 10.2174/0929867327999200817102154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/21/2020] [Accepted: 07/21/2020] [Indexed: 11/22/2022]
Abstract
Drug repositioning is a strategy to identify new uses for approved or investigational drugs that are used off-label outside the scope of the original medical indication. In this review, we report the most relevant studies about drug repositioning in hematology, reporting the signalling pathways and molecular targets of these drugs, and describing the biological mechanisms which are responsible for their anticancer effects. Although the majority of studies on drug repositioning in hematology concern acute myeloid leukemia and multiple myeloma, numerous studies are present in the literature on the possibility of using these drugs also in other hematological diseases, such as acute lymphoblastic leukemia, chronic myeloid leukemia, and lymphomas. Numerous anti-infectious drugs and chemical entities used for the therapy of neurological or endocrine diseases, oral antidiabetics, statins and medications used to treat high blood pressure and heart failure, bisphosphonate and natural substance such as artemisin and curcumin, have found a place in the treatment of hematological diseases. Moreover, several molecules drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo.
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Affiliation(s)
- Alessandro Allegra
- Department of Human Pathology in Adulthood and Childhood, University of Messina, Messina, Italy
| | - Chiara Imbesi
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Roberta Ettari
- Department of Chemical, Biological, Pharmaceutical and Environmental Chemistry, University of Messina, Messina, Italy
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Na HK, Won SH, Ahn JY, Kim GH, Jung KW, Lee JH, Kim DH, Choi KD, Song HJ, Lee GH, Jung HY, Kim HJ. Clinical course of duodenal mucosa-associated lymphoid tissue lymphoma: Comparison with gastric mucosa-associated lymphoid tissue lymphoma. J Gastroenterol Hepatol 2021; 36:406-412. [PMID: 32573049 DOI: 10.1111/jgh.15157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 06/09/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM There are few cases of duodenal mucosa-associated lymphoid tissue (MALT) lymphoma reported in the literature, and little is known about the clinical course of this disease. Here, we aimed to characterize the clinical features of duodenal MALT lymphoma by comparison with gastric MALT lymphoma. METHODS Thirteen patients diagnosed with duodenal MALT lymphoma at Asan Medical Center from March 1997 to February 2017 were included in this retrospective study, along with patients with gastric MALT lymphoma, matched by age and sex at a 1:10 ratio. RESULTS Median age of patients with duodenal MALT lymphoma was 49 (range 20-72) years, and 53.8% (7/13) were male. Comparison of patient characteristics indicated that Helicobacter pylori infection (46.2% vs 90.8%, P < 0.001) and lymph node metastasis (23.1% vs 5.4%, P = 0.049) rates differed between patients with duodenal and gastric MALT lymphoma. Overall complete remission (61.5% vs 86.2%, P = 0.021) and complete remission after initial H. pylori eradication therapy (50% vs 87.7%, P = 0.037) were significantly lower in patients with duodenal than gastric MALT lymphoma. Complications including bleeding, stricture, and transformation to high-grade lymphoma occurred in a total of seven patients (4.9%), with a higher incidence in patients with duodenal than gastric MALT lymphoma (38.5% vs 1.5%, P < 0.001). CONCLUSIONS Duodenal MALT lymphoma is very rare, and treatment outcomes appear to be inferior to those of gastric MALT lymphoma.
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Affiliation(s)
- Hee Kyong Na
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Sung Hyun Won
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Ji Yong Ahn
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Ga Hee Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Kee Wook Jung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Jeong Hoon Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Do Hoon Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Kee Don Choi
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Ho June Song
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Gin Hyug Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Hwoon-Yong Jung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Asan Digestive Disease Research Institute, Seoul, Korea
| | - Hwa Jung Kim
- Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Yokota K, Namikawa T, Maeda M, Tanioka N, Iwabu J, Uemura S, Munekage M, Maeda H, Kitagawa H, Kobayashi M, Hanazaki K. Synchronous duodenal mucosa-associated lymphoid tissue lymphoma and gastric cancer. Clin J Gastroenterol 2021; 14:109-114. [PMID: 32959165 DOI: 10.1007/s12328-020-01241-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/11/2020] [Indexed: 02/05/2023]
Abstract
Duodenal mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare tumor. Herein, we report multidisciplinary treatment of a patient with synchronous development of primary MALT lymphoma of the duodenum and gastric cancer. A 70-year-old woman was referred to our hospital for examination of a gastric cancer initially diagnosed by a local medical doctor. Esophagogastroduodenoscopy showed an elevated lesion with a central ulcer in the lower body of the stomach, and a partially whitish aggregated lesion in the descending portion of the duodenum. Histopathological examination of biopsy specimens from the gastric lesion showed moderately differentiated adenocarcinoma, and duodenal specimens showed low-grade MALT lymphoma composed of atypical lymphoid cells with a lymphoepithelial lesion. The patient underwent distal gastrectomy with regional lymph node dissection for the gastric cancer. Histological examination showed muscularis propria invading adenocarcinoma with two lymph node metastases. After operation, four courses of systemic rituximab treatment were administered for the MALT lymphoma, followed by adjuvant S-1 (tegafur/gimeracil/oteracil) chemotherapy for the gastric cancer. In the 4 months after operation, the patient was well with no evidence of recurrence. To the best of our knowledge, this is the second reported case of synchronous gastric adenocarcinoma and duodenal MALT lymphoma in the English literature.
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Affiliation(s)
- Keiichiro Yokota
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Tsutomu Namikawa
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
| | - Masahiro Maeda
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Nobuhisa Tanioka
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Jun Iwabu
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Sunao Uemura
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Masaya Munekage
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Hiromichi Maeda
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Hiroyuki Kitagawa
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
| | - Michiya Kobayashi
- Department of Human Health and Medical Sciences, Kochi Medical School, Nankoku, Kochi, Japan
| | - Kazuhiro Hanazaki
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan
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Amani N, Shokrzadeh M, Shaki F. Clarithromycin effectively enhances doxorubicin-induced cytotoxicity and apoptosis in MCF7 cells through dysregulation of autophagy. Adv Med Sci 2020; 65:235-243. [PMID: 32252007 DOI: 10.1016/j.advms.2020.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 01/13/2020] [Accepted: 03/21/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Use of autophagy inhibitors in combination with chemotherapy has become a novel chemotherapeutic strategy. In this study, we aimed to determine whether the effectiveness of doxorubicin (DOX) is augmented by clarithromycin (CAM) in MCF7 cells and the molecular mechanisms involved. MATERIALS AND METHODS Combined cytotoxicity of CAM and DOX was assessed by MTT assay and was analyzed using the Chou-Talalay's method. To clarify the underlying mechanisms, several factors, including apoptosis (Annexin V/propidium iodide staining), intracellular level of DOX (spectrofluorimetry) and P-glycoprotein activity (Rhodamin 123 efflux assay) were measured. In addition, autophagy was evaluated by intracellular labeling with anti-LC3II and LysoTrackerGreen (LTG) staining and analyzed by flowcytometry. RESULTS The anti-proliferation effect of DOX was synergistically enhanced by CAM in MCF7 cells and was associated with an increase in the apoptotic cell death. However, the intracellular level of DOX remained unchanged in the presence of CAM. Based on the findings, 100 μM of CAM did not exhibit any inhibitory effects on P-glycoprotein activity. Flow cytometric analysis indicated that DOX at IC20 concentration induced the autophagy flux, as confirmed by the increased level of LC3II and LTG signals. Moreover, combined treatment with DOX and CAM resulted in more pronounced LTG signals, but no change in LC3II. These results indicate that CAM blocks the autophagy flux induced by DOX. CONCLUSIONS These findings suggest that suppression of autophagy by CAM may promote chemotherapeutic outcome in breast cancer. However, further investigations are needed to evaluate the application of CAM in adjuvant breast cancer therapy.
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Affiliation(s)
- Nahid Amani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Shokrzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh Shaki
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
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Van Nuffel AMT, Sukhatme V, Pantziarka P, Meheus L, Sukhatme VP, Bouche G. Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent. Ecancermedicalscience 2015; 9:513. [PMID: 25729426 PMCID: PMC4341996 DOI: 10.3332/ecancer.2015.513] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Indexed: 12/17/2022] Open
Abstract
Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients.
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Affiliation(s)
| | | | - Pan Pantziarka
- Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium
- The George Pantziarka TP53 Trust, London KT1 2JP, UK
| | - Lydie Meheus
- Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium
| | - Vikas P Sukhatme
- GlobalCures, Inc, Newton, MA 02459, USA
- Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, MA 02215, USA
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Campuzano-Maya G. Hematologic manifestations of Helicobacter pylori infection. World J Gastroenterol 2014; 20:12818-12838. [PMID: 25278680 PMCID: PMC4177465 DOI: 10.3748/wjg.v20.i36.12818] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Revised: 06/10/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is the most common infection in humans, with a marked disparity between developed and developing countries. Although H. pylori infections are asymptomatic in most infected individuals, they are intimately related to malignant gastric conditions such as gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to benign diseases such as gastritis and duodenal and gastric peptic ulcers. Since it was learned that bacteria could colonize the gastric mucosa, there have been reports in the medical literature of over 50 extragastric manifestations involving a variety medical areas of specialization. These areas include cardiology, dermatology, endocrinology, gynecology and obstetrics, hematology, pneumology, odontology, ophthalmology, otorhinolaryngology and pediatrics, and they encompass conditions with a range of clear evidence between the H. pylori infection and development of the disease. This literature review covers extragastric manifestations of H. pylori infection in the hematology field. It focuses on conditions that are included in international consensus and management guides for H. pylori infection, specifically iron deficiency, vitamin B12 (cobalamin) deficiency, immune thrombocytopenia, and MALT lymphoma. In addition, there is discussion of other conditions that are not included in international consensus and management guides on H. pylori, including auto-immune neutropenia, antiphospholipid syndrome, plasma cell dyscrasias, and other hematologic diseases.
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Carman R, Snyder J, Davidson M. Primary mucosa-associated lymphoid tumor lymphoma of the duodenum: a rare presentation of non-Hodgkin's lymphoma. J Clin Oncol 2011; 29:e226-9. [PMID: 21205760 DOI: 10.1200/jco.2010.31.9525] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Ishimatsu Y, Mukae H, Matsumoto K, Harada T, Hara A, Hara S, Amenomori M, Fujita H, Sakamoto N, Hayashi T, Kohno S. Two Cases With Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma Successfully Treated With Clarithromycin. Chest 2010; 138:730-3. [DOI: 10.1378/chest.09-2358] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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9
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Duodenal MALT Lymphoma Presenting With Obstructive Jaundice: Report of a Case and Review of the Literature. J Gastrointest Cancer 2008; 38:28-31. [DOI: 10.1007/s12029-008-9012-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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10
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Woo KH, Kim JH, Yoon SB, Jang JH, Lee DH, Hong SH, Baek IH. Duodenal mucosa-associated lymphoid tissue lymphoma: a case report. Korean J Intern Med 2007; 22:296-9. [PMID: 18309692 PMCID: PMC2687664 DOI: 10.3904/kjim.2007.22.4.296] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Primary duodenal mucosa associated lymphoid tissue (MALT) lymphoma is very rare, and little is known about its clinical course or effective treatment. We describe a case of primary duodenal MALT lymphoma that was resistant to Helicobacter pylon (H. pylori) eradication and regressed after chemotherapy with cyclophosphamide, vincristine, and prednisolone (CVP). A 71-year-old woman was referred to our department because of epigastric pain and dyspepsia. Gastroduodenoscopy revealed an irregular mucosal nodular lesion with ulceration extending from the bulb to the second portion of the duodenum. Histopathological examination of a biopsy specimen disclosed low-grade MALT lymphoma composed of atypical lymphoid cells with lymphoepithelial lesion. Abdominal CT scans revealed 0.5 to 1.5 cm lymph nodes in the peritoneal cavity, suggestive of lymph node metastasis. We successfully eradicated H. pylori but did not see signs of remission. We administered systemic CVP chemotherapy every 3 weeks. After 6 courses of CVP, the patient achieved complete remission and was followed up without recurrence for about a year.
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Affiliation(s)
- Kyung Hee Woo
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
| | - Jung Han Kim
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
| | - Seong Bo Yoon
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
| | - Joo Hyun Jang
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
| | - Dong Hun Lee
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
| | - Seong Ho Hong
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
| | - Il Hyun Baek
- Department of Internal Medicine, Kangnam Sacred-heart Hospital, College of Medicine Hallym University, Seoul, Korea
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Azar C, Soweid A, Berro Z, Salem ZMK, Geara FB, Kattar MM, Hashash JG, Barada KA. Duodenal mucosa-associated lymphoid tissue lymphoma successfully treated by radiation therapy. CLINICAL LYMPHOMA & MYELOMA 2007; 7:428-431. [PMID: 17621410 DOI: 10.3816/clm.2007.n.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Duodenal mucosa-associated lymphoid tissue (MALT) lymphoma is very rare, and little is known about its clinical characteristics, endoscopic and endosonographic features, and treatment. We hereby report a case of duodenal MALT lymphoma successfully treated by radiation therapy (RT). The patient was referred to us with epigastric pain and positive fecal occult blood testing. His symptoms failed to resolve with eradication therapy for a Helicobacter pylori infection that was diagnosed by a gastric biopsy performed elsewhere. Endoscopy at our institution revealed hypertrophy of the duodenal folds with erosions involving a third of the circumference few centimeters beyond the ampulla of Vater. Histopathologic and immunophenotypic features were consistent with a MALT lymphoma. There was no evidence of a H. pylori infection by gastric biopsy and urea breath test. Computed tomography scan of the abdomen and pelvis was normal. Endoscopic ultrasound showed thickening of the duodenal wall and hypoechoic infiltration into the submucosal layer. The patient was treated with RT with a complete response. Two and a half years later, he remains in complete clinical, endoscopic, and histopathologic remission. This case illustrates the importance of RT in patients with duodenal MALT lymphoma whose disease did not respond to H. pylori eradication.
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Affiliation(s)
- Cecilio Azar
- Department of Internal Medicine, American University of Beirut Medical Center, Hamra Street, Beirut 110, 32090 Lebanon
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