Abstract
Breast cancer, the first most common malignant tumor in women worldwide. Many etiological factors such as a wide spectrum of clinical manifestations caused by family clustering, hormonal factors, physiology changed, environmental inducers, and life styles. Although there are many FDA-approval drugs for breast cancers. Tumors are heterogenous and individual has inherited different genetic background. Thus, it is hard to find an effective treatment and it may recurrent after recovery from first treatment.
Key words
breast cancer, autophagy, autophagy-related inhibitors, chemotherapy
Introduction
The mortality rate exceeds 144,000 cases and most of the breast cancer (BC) cases are resistant to traditional chemotherapy and radiotherapy. A wide variety of chemotherapeutic agents have been tried and are in use, including tamoxifen, docetaxel, anthracyclines (i.e. doxorubicin, and epirubicin), taxanes (i.e. paclitaxel, and docetaxel), 5-fluorouracil, cyclophosphamide, and carboplatin. No regimen has been proved to be curative. Often, the response rate and prolongation of survival are minimal (a few months or less), and there is a significant morbidity associated with poor treatment effects. Surgical resection is considered the first-line options for early tumors, although there is no agreement on which is the best approach. Interestingly, triple negative has been reported has higher chemo-resistance than other type of breast cancers with low autophagy activity [1,2]. Antiestrogen resistant cell lines exhibit increased basal autophagy when compared with their antiestrogen sensitive parental cells [3]. Study has shown to manipulate transient receptor potential channel 5 (TRPC5), a Ca2+ permeable cation channel, which helps in promotes autophagic activity [4]. Studies also demonstrate the breast cancer usually prosurvival after autophagy activity increase by various therapeutics [5-7]. Moreover, Tamoxifen and Faslodex (ICI) both induce autophagy in ER+ breast cancer cells without [3,5,8-11]. There are small molecules which has been in FDA-approval drug lists and applied in clinical trial in different diseases (Table 1 and 2).
Table 1. Autophagy inhibitors during autophagy pathway. Modified from [13].
Name | Mechanism | |
3-Methyladenine | phosphoinositide3-kinase (PI3) inhibitor | Autophagosome formation |
Wortmannin | PI3-kinase inhibitor | Autophagosome formation |
LY294002 | PI3-kinase inhibitor | Autophagosome formation |
SBI-0206965 | Unc-51-like kinase 1 (ULK1) Inhibitor | Autophagosome formation |
Spautin-1 | ubiquitin-specific peptidases (USP10) and (USP13) inhibitor | Autophagosome formation |
SAR405 | Vacuolar Protein Sorting Protein 18 and 34 (Vps18 and Vps34) inhibitor | Autophagosome formation |
NSC185058 | autophagy-related gene 4 (ATG4) inhibitor | Autophagosome formation |
Verteporfin | Unknown | Autophagosome formation and accumulation |
ROC325 | Unknown | Lysosome |
Lys05 | Unknown | Lysosome |
Chloroquine | Unknown | Lysosome |
Hydroxychloroquine | Unknown | Lysosome |
Table 2. Current Hydroxychloroquine (HCQ) clinical trials. Modified from [13].
Treatment | Condition | Phase Trial | Reference # at ClinicalTrials.gov |
HCQ + sunitinib malate | Adult solid neoplasm | I | NCT00813423 |
HCQ + vorinostat | Malignant solid tumor | I | NCT01023737 |
HCQ + sirolimus or vorinostat | Advanced cancers | I | NCT01266057 |
HCQ + Protein kinase B (Akt) inhibitor MK-2206 dihydrochloride (MK2206) | Advanced cancers | I | NCT01480154 |
HCQ as a single agent | Estrogen receptor positive breast cancer | I | NCT02414776 |
HCQ + gemcitabine | Advanced adenocarcinoma | I/II | NCT01506973 |
HCQ + Interleukin 2(IL-2) | Renal cell carcinoma | I/II | NCT01550367 |
HCQ + vorinostat | Colorectal cancer | I/II | NCT02316340 |
HCQ + gemcitabine/carboplatin | Small cell lung cancer | I/II | NCT02722369 |
HCQ + capecitabine | Pancreatic carcinoma | II | NCT01494155 |
HCQ as a single agent | Prostate cancer | II | NCT00726596 |
HCQ + Abraxane and gemcitabine | Pancreatic carcinoma | II | NCT01978184 |
Antiestrogen resistant cell lines exhibit increased basal autophagy. Study had demonstrated combination of Tamoxifen or Faslodex (ICI) with hydroxychloroquine (HCQ) had different anti-estrogen responsiveness in vitro or in vivo which may affect by tumor microenvironment (i.e. chemokines, macrophage development/activity [12]. Inhibiting autophagy via autophagy-related genes (i.e. autophagy-related gene (Atg) 5, Atg7, and p62/SQSTM1) silencing potentiated antiestrogen-mediated cell death, indicating that antiestrogen stimulated autophagy is prosurvival and a critical mechanism of therapy resistance [3]. Overall, it indicated that increased in autophagy activity in early recurring breast cancer when compared with breast cancer that never recurs. Moreover, elevated p62 is significantly correlated with poor survival in breast cancer patients [12], suggesting a role for autophagy in breast cancer reoccurrence. Manipulation of autophagy activity can be a potential therapy for chemotherapy in vitro or in vivo. Therefore, diagnosis or detection at an early stage is crucial to allow the application of treatments for increasing the life expectancy of the patient.
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